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Wang, Xiansong, Wei Hu, Xiangchun Li, Dan Huang, Qing Li, Hung Chan, Judeng Zeng et al. "Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution". Cancer Research 82, n.º 8 (3 de marzo de 2022): 1482–91. http://dx.doi.org/10.1158/0008-5472.can-21-3458.
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Abstract Cancer-related genes are under intense evolutionary pressure. In this study, we conjecture that X-linked tumor suppressor genes (TSG) are not protected by the Knudson's two-hit mechanism and are therefore subject to negative selection. Accordingly, nearly all mammalian species exhibited lower TSG-to-noncancer gene ratios on their X chromosomes compared with nonmammalian species. Synteny analysis revealed that mammalian X-linked TSGs were depleted shortly after the emergence of the XY sex-determination system. A phylogeny-based model unveiled a higher X chromosome-to-autosome relocation flux for human TSGs. This was verified in other mammals by assessing the concordance/discordance of chromosomal locations of mammalian TSGs and their orthologs in Xenopus tropicalis. In humans, X-linked TSGs are younger or larger in size. Consistently, pan-cancer analysis revealed more frequent nonsynonymous somatic mutations of X-linked TSGs. These findings suggest that relocation of TSGs out of the X chromosome could confer a survival advantage by facilitating evasion of single-hit inactivation. Significance: This work unveils extensive trafficking of TSGs from the X chromosome to autosomes during evolution, thus identifying X-linked TSGs as a genetic Achilles' heel in tumor suppression.
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Cho, Seong Beom. "Uncovering Oncogenic Mechanisms of Tumor Suppressor Genes in Breast Cancer Multi-Omics Data". International Journal of Molecular Sciences 23, n.º 17 (25 de agosto de 2022): 9624. http://dx.doi.org/10.3390/ijms23179624.
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Tumor suppressor genes (TSGs) are essential genes in the development of cancer. While they have many roles in normal cells, mutation and dysregulation of the TSGs result in aberrant molecular processes in cancer cells. Therefore, understanding TSGs and their roles in the oncogenic process is crucial for prevention and treatment of cancer. In this research, multi-omics breast cancer data were used to identify molecular mechanisms of TSGs in breast cancer. Differentially expressed genes and differentially coexpressed genes were identified in four large-scale transcriptomics data from public repositories and multi-omics data analyses of copy number, methylation and gene expression were performed. The results of the analyses were integrated using enrichment analysis and meta-analysis of a p-value summation method. The integrative analysis revealed that TSGs have a significant relationship with genes of gene ontology terms that are related to cell cycle, genome stability, RNA processing and metastasis, indicating the regulatory mechanisms of TSGs on cancer cells. The analysis frame and research results will provide valuable information for the further identification of TSGs in different types of cancers.
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Güvenç, Canan, Fien Neckebroeck, Asier Antoranz, Marjan Garmyn, Joost van den Oord y Francesca Maria Bosisio. "Bona Fide Tumor Suppressor Genes Hypermethylated in Melanoma: A Narrative Review". International Journal of Molecular Sciences 22, n.º 19 (1 de octubre de 2021): 10674. http://dx.doi.org/10.3390/ijms221910674.
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Loss-of-function events in tumor suppressor genes (TSGs) contribute to the development and progression of cutaneous malignant melanoma (CMM). Epigenetic alterations are the major mechanisms of TSG inactivation, in particular, silencing by promoter CpG-island hypermethylation. TSGs are valuable tools in diagnosis and prognosis and, possibly, in future targeted therapy. The aim of this narrative review is to outline bona fide TSGs affected by promoter CpG-island hypermethylation and their functional role in the progression of CMM. We conducted a systematic literature review to identify studies providing evidence of bona fide TSGs by cell line or animal experiments. We performed a broad first search and a gene-specific second search, supplemented by reference checking. We included studies describing bona fide TSGs in CMM with promoter CpG-island hypermethylation in which inactivating mechanisms were reported. We extracted data about protein role, pathway, experiments conducted to meet the bona fide criteria and hallmarks of cancer acquired by TSG inactivation. A total of 24 studies were included, describing 24 bona fide TSGs silenced by promoter CpG-island hypermethylation in CMM. Their effect on cell proliferation, apoptosis, growth, senescence, angiogenesis, migration, invasion or metastasis is also described. These data give further insight into the role of TSGs in the progression of CMM.
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Liyanage, Chamikara, Asanga Wathupola, Sanjayan Muraleetharan, Kanthi Perera, Chamindie Punyadeera y Preethi Udagama. "Promoter Hypermethylation of Tumor-Suppressor Genes p16INK4a, RASSF1A, TIMP3, and PCQAP/MED15 in Salivary DNA as a Quadruple Biomarker Panel for Early Detection of Oral and Oropharyngeal Cancers". Biomolecules 9, n.º 4 (12 de abril de 2019): 148. http://dx.doi.org/10.3390/biom9040148.
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Silencing of tumor-suppressor genes (TSGs) by DNA promoter hypermethylation is an early event in carcinogenesis; hence, TSGs may serve as early tumor biomarkers. We determined the promoter methylation levels of p16INK4a, RASSF1A, TIMP3, and PCQAP/MED15 TSGs in salivary DNA from oral cancer (OC) and oropharyngeal cancer (OPC) patients, using methylation-specific PCR coupled with densitometry analysis. We assessed the association between DNA methylation of individual TSGs with OC and OPC risk factors. The performance and the clinical validity of this quadruple-methylation marker panel were evaluated in discriminating OC and OPC patients from healthy controls using the CombiROC web tool. Our study reports that RASSF1A, TIMP3, and PCQAP/MED15 TSGs were significantly hypermethylated in OC and OPC cases compared to healthy controls. DNA methylation levels of TSGs were significantly augmented by smoking, alcohol use, and betel quid chewing, indicating the fact that frequent exposure to risk factors may drive oral and oropharyngeal carcinogenesis through TSG promoter hypermethylation. Also, this quadruple-methylation marker panel of p16INK4a, RASSF1A, TIMP3, and PCQAP/MED15 TSGs demonstrated excellent diagnostic accuracy in the early detection of OC at 91.7% sensitivity and 92.3% specificity and of OPC at 99.8% sensitivity and 92.1% specificity from healthy controls.
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Li, He, Yilin Mao, Yu Wang, Kai Fan, Hongtao Shi, Litao Sun, Jiazhi Shen, Yaozong Shen, Yang Xu y Zhaotang Ding. "Environmental Simulation Model for Rapid Prediction of Tea Seedling Growth". Agronomy 12, n.º 12 (14 de diciembre de 2022): 3165. http://dx.doi.org/10.3390/agronomy12123165.
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Accurate and effective monitoring of environmental parameters in tea seedling greenhouses is an important basis for regulating the seedling environment, which is crucial for improving the seedling growth quality. This study proposes a tea seedling growth simulation (TSGS) model based on deep learning. The Internet of Things system was used to measure environmental change during the whole seedling process. The correlation between the environmental parameters and the biomass growth of tea seedlings in various varieties was analyzed. A CNN-LSTM network was proposed to build the TSGS model of light, temperature, water, gas, mineral nutrition, and growth biomass. The results showed that: (1) the average correlation coefficients of air temperature, soil temperature, and soil moisture with the biomass growth of tea seedlings were 0.78, 0.84, and −0.63, respectively, which were three important parameters for establishing the TSGS model. (2) For evaluating the TSGS model of a single variety, the accuracy of ZM’s TSGS based on the CNN-LSTM network was the highest (Rp2 = 0.98, RMSEP = 0.14). (3) For evaluating the TSGS model of multiple varieties, the accuracy of TSGS based on the CNN-LSTM network was the highest (Rp2 = 0.96, RMSEP = 0.17). This study provided effective technical parameters for intelligent control of tea-cutting growth and a new method for rapid breeding.
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Fijneman, Remond J. A. "Genetic Predisposition to Sporadic Cancer: How to Handle Major Effects of Minor Genes?" Analytical Cellular Pathology 27, n.º 5-6 (1 de enero de 2005): 281–92. http://dx.doi.org/10.1155/2005/737191.
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Predisposition to non-familial, sporadic cancer is strongly influenced by multiple tumor susceptibility genes (TSGs), each with apparently minor effects on the cancer phenotype. Sequence analysis of the human genome has yielded numerous single nucleotide polymorphisms (SNPs), raising the expectation that new low-penetrance TSGs will be identified that can be used to estimate an individuals cancer risk. However, mouse models for human cancer showed that the effects of many low-penetrance TSGs are highly variable due to their involvement in epistatic interactions. Together, these interacting TSGs form large molecular networks, which represent cancer-associated biological modules that influence the tumorigenic process. As a consequence, although allelic variation in one TSG on a permissive genetic Background can have major effects on tumor development, the net effect of allelic variation in multiple interacting TSGs remains hard to predict. Therefore, the predictive value of SNP-analysis to estimate an individuals cancer risk will be restricted to those TSGs that exhibit single-gene effects. New strategies need to be developed to evaluate cancer risk associated with biological modules that are influenced by TSG-networks.
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Wang, Li-Hui, Chun-Fu Wu, Nirmal Rajasekaran y Young Kee Shin. "Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview". Cellular Physiology and Biochemistry 51, n.º 6 (2018): 2647–93. http://dx.doi.org/10.1159/000495956.
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Cancer is a disease caused by the accumulation of genetic and epigenetic changes in two types of genes: tumor suppressor genes (TSGs) and proto-oncogenes. Extensive research has been conducted over the last few decades to elucidate the role of TSGs in cancer development. In cancer, loss of TSG function occurs via the deletion or inactivation of two alleles, according to Knudson’s two-hit model hypothesis. It has become clear that mutations in TSGs are recessive at the level of an individual cell; therefore, a single mutation in a TSG is not sufficient to cause carcinogenesis. However, many studies have identified candidate TSGs that do not conform with this standard definition, including genes inactivated by epigenetic silencing rather than by deletion. In addition, proteasomal degradation by ubiquitination, abnormal cellular localization, and transcriptional regulation are also involved in the inactivation of TSGs. This review incorporates these novel additional mechanisms of TSG inactivation into the existing two-hit model and proposes a revised multiple-hit model that will enable the identification of novel TSGs that can be used as prognostic and predictive biomarkers of cancer.
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Salavaty, Abbas, Niloufar Mohammadi, Mozhdeh Shahmoradi y Maryam Naderi Soorki. "Bioinformatic Analysis of Circadian Expression of Oncogenes and Tumor Suppressor Genes". Bioinformatics and Biology Insights 11 (1 de enero de 2017): 117793221774699. http://dx.doi.org/10.1177/1177932217746991.
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Background: Circadian rhythms are physiological and behavioral cycles with a period of approximately 24 hours that control various functions including gene expression. Circadian disruption is associated with a variety of diseases, especially cancer. Although some of the oncogenes and tumor suppressor genes (TSGs) are known as clock-controlled genes (CCGs), the analysis and annotation of circadian expression of most human oncogenes and TSGs are still lacking. This study aims to investigate the circadian expression of a list of human oncogenes and TSGs. Methods: A bioinformatic analysis was conducted on a gene library comprising 120 genes to investigate the circadian expression of human oncogenes and TSGs. To achieve this purpose, the genotranscriptomic data were retrieved from COSMIC and analyzed by R statistical software. Furthermore, the acquired data were analyzed at the transcriptomic and proteomic levels using several publicly available databases. Also, the significance of all analyses was confirmed statistically. Results: Altogether, our results indicated that 7 human oncogenes/TSGs may be expressed and function in a circadian manner. These oncogenes/TSGs showed a circadian expression pattern at CircaDB database and associated with at least one of the circadian genes/CCGs based on both genotranscriptomic and correlation analyses. Conclusions: Although 4 of 7 finally outputted genes have been previously reported to be clock controlled, heretofore there is no report about the circadian expression of 3 other genes. Considering the importance of oncogenes/TSGs in the initiation and progression of cancer, further studies are suggested for the identification of exact circadian expression patterns of these 3 human oncogenes/TSGs.
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Sun, Qingrong, Md Nazim Uddin, Mengyuan Li, Xiaosheng Wang y Maode Lai. "Computational Identification of Tumor Suppressor Genes Based on Gene Expression Profiles in Normal and Cancerous Gastrointestinal Tissues". Journal of Oncology 2020 (22 de julio de 2020): 1–12. http://dx.doi.org/10.1155/2020/2503790.
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Cancer prevails in various gastrointestinal (GI) organs, such as esophagus, stomach, and colon. However, the small intestine has an extremely low cancer risk. It is interesting to investigate the molecular cues that could explain the significant difference in cancer incidence rates among different GI tissues. Using several large-scale normal and cancer tissue genomics datasets, we compared the gene expression profiling between small intestine and other GI tissues and between GI cancers and normal tissues. We identified 17 tumor suppressor genes (TSGs) which showed significantly higher expression levels in small intestine than in other GI tissues and significantly lower expression levels in GI cancers than in normal tissues. These TSGs were mainly involved in metabolism, immune, and cell growth signaling-associated pathways. Many TSGs had a positive expression correlation with survival prognosis in various cancers, confirming their tumor suppressive function. We demonstrated that the downregulation of many TSGs was associated with their hypermethylation in cancer. Moreover, we showed that the expression of many TSGs inversely correlated with tumor purity and positively correlated with antitumor immune response in various cancers, suggesting that these TSGs may exert their tumor suppressive function by promoting antitumor immunity. Furthermore, we identified a transcriptional regulatory network of the TSGs and their master transcriptional regulators (MTRs). Many of MTRs have been recognized as tumor suppressors, such as HNF4A, ZBTB7A, p53, and RUNX3. The TSGs could provide new molecular cues associated with tumorigenesis and tumor development and have potential clinical implications for cancer diagnosis, prognosis, and treatment.
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Li, Qian, Yizhi Zhang, Jinglu Hu, Bochuan Yuan, Pengcheng Zhang, Yaxin Wang, Xu Jin, Lina Du y Yiguang Jin. "The Improved Brain-Targeted Drug Delivery of Edaravone Temperature-Sensitive Gels by Ultrasound for γ-ray Radiation-Induced Brain Injury". Pharmaceutics 14, n.º 11 (25 de octubre de 2022): 2281. http://dx.doi.org/10.3390/pharmaceutics14112281.
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Radiation-induced brain injury (RBI) is a common neurological disease caused by ionizing radiation (IR). Edaravone (EDA) is a free radical scavenger, has the potential to treat RBI. EDA loaded temperature-sensitive gels (TSGs) were prepared for subcutaneous injection to improve inconvenient administration of intravenous infusion. RBI mice model was established by irradiation of 60Co γ-ray on head. EDA TSGs could improve spontaneous behavior, learning and memory and anxiety of RBI mice by behavior tests, including the open field test, the novel object recognition test, the elevated plus maze test and the fear conditioning test. The therapeutic effects were enhanced with the assistance of ultrasound. Alleviative pathological changes, decreased the expression of Molondialdehyde (MDA) and Interleukin-6 (IL-6) in the hippocampus of brain, indicated reduced oxidative stress and inflammatory response with the treatment of EDA TSGs and ultrasound. Moreover, ultrasound was superior to the use of EDA TSGs. Safe and effective EDA TSGs were prepared for RBI, and the feasibility of brain-targeted drug delivery enhanced by ultrasound was preliminarily demonstrated in this study.
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Las-Casas, Pedro, Alok Gautum Kumbhare, Rodrigo Fonseca y Sharad Agarwal. "LLexus: an AI agent system for incident management". ACM SIGOPS Operating Systems Review 58, n.º 1 (14 de agosto de 2024): 23–36. http://dx.doi.org/10.1145/3689051.3689056.
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When operating a software service on a cloud, the complexity of keeping multiple distributed components responsive is a significant challenge for engineering teams. Engineers frequently rely on Troubleshooting Guides (TSGs) to navigate how to mitigate performance or outage incidents. However, the effectiveness of TSGs is often hindered by their length, implicit reliance on tribal knowledge, and the variable quality of their content. This paper introduces LLexus, an agent-based AI system to automate the execution of TSGs.
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Tanić, Nikola, Tatjana Dramićanin, Nejla Ademović, Tijana Tomić, Blagoje Murganić, Zorka Milovanović, Milica Nedeljković y Nasta Tanić. "The impact of TP53 and PTEN tumor suppressor genes on response to different breast cancer treatment modalities". Биомедицинска истраживања 13, n.º 2 (2022): 105–17. http://dx.doi.org/10.5937/bii2202105t.
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ntroduction. Breast cancer (BC) is the most frequent type of malignancy and the leading cause of cancer related death among women worldwide. BC is exceptionally heterogeneous disease and therefore distinct treatment modalities are necessary to address these differences. The aim of our study was to investigate the impact of TP53 and PTEN tumor suppressor genes (TSGs) inactivation on BC response to different treatment modalities and their possible cooperation, on post-operative BC samples. Methods. Patients were classified, based on applied adjuvant therapy, into four distinct groups: those that received hormonal therapy (HT) only, hormonal therapy combined with chemotherapy (HT/CHT), hormonal therapy combined with chemo and biological therapy (HT/CHT/H), and other systemic therapies that exclude HT. Functional inactivation of TP53 and PTEN TSG's were studied by mutation, loss of heterozygosity (LOH) and hypermethylation analysis. Results. Our results revealed that TP53 gene was altered in 63 out of 90 specimens (70%), while the frequency of PTEN alterations was slightly lower, 54 out of 90 (60%). Simultaneous inactivation was detected in 43 tested samples (48%) with significant association between two analyzed TSGs. Further, we found that TP53 status has significant influence on patients' therapy response. Contrary to this, no significance was found between mutational status of PTEN and various treatment modalities. However, significant association was found between the type of applied therapy and simultaneous alterations of these two TSGs (p = 0.00001). Conclusion. Patients with wtTP53 show significantly better therapy response regardless of the type of therapy, compared to carriers of altered TPp53 gene.
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Yang, Xiaoqin, Yun Ye, Guiping Wang, Hong Huang, Dekuang Yu y Shuang Liang. "VeryGene: linking tissue-specific genes to diseases, drugs, and beyond for knowledge discovery". Physiological Genomics 43, n.º 8 (abril de 2011): 457–60. http://dx.doi.org/10.1152/physiolgenomics.00178.2010.
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In addition to many other genes, tissue-specific genes (TSGs) represent a set of genes of great importance for human physiology. However, the links among TSGs, diseases, and potential therapeutic agents are often missing, hidden, or too scattered to find. There is a need to establish a knowledgebase for researchers to share this and additional information in order to speed up discovery and clinical practice. As an initiative toward systems biology, the VeryGene web server was developed to fill this gap. A significant effort has been made to integrate TSGs from two large-scale data analyses with respective information on subcellular localization, Gene Ontology, Reactome, KEGG pathway, Mouse Genome Informatics (MGI) Mammalian Phenotype, disease association, and targeting drugs. The current release carefully selected 3,960 annotated TSGs derived from 127 normal human tissues and cell types, including 5,672 gene-disease and 2,171 drug-target relationships. In addition to being a specialized source for TSGs, VeryGene can be used as a discovery tool by generating novel inferences. Some inherently useful but hidden relations among genes, diseases, drugs, and other important aspects can be inferred to form testable hypotheses. VeryGene is available online at http://www.verygene.com .
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Zucker, Mark R., Maria A. Perry, Arielle Elkrief, Anton Safonov, Rohit Thummalapalli, Samuel I. Gould, Debyani Chakravarty et al. "Abstract 1202: Signatures of selection for biallelic inactivation in tumor suppressor genes across cancer types". Cancer Research 84, n.º 6_Supplement (22 de marzo de 2024): 1202. http://dx.doi.org/10.1158/1538-7445.am2024-1202.
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Abstract Background: The canonical model of tumor suppressor gene (TSG)-mediated oncogenesis, Knudson’s “two hit hypothesis,” posits that loss of both alleles is necessary for TSG inactivation. Many key TSGs accordingly exhibit near universal biallelic loss in associated cancers (e.g., APC in colorectal cancer and RB1 in retinoblastoma). However, because the majority of large-scale cancer genomics studies have utilized non-allele-specific copy number analysis methods, neither the extent of biallelic inactivation across TSGs, nor patterns of selective pressure for biallelic inactivation of TSGs, nor the functional and translational consequences of biallelic inactivation, are well-understood. Methods: Here, through allele-specific analysis of sequencing data from 48,179 cancer patients, we define the prevalence, selective pressure for, and functional consequences of biallelic inactivation across TSGs. We classify TSGs according to their patterns of selection for or against biallelic inactivation across cancer types. Finally, we investigate in detail the association of biallelic status with gene expression and clinical outcome for two TSGs, KEAP1 (in lung adenocarcinoma) and APC (in lung and prostate adenocarcinoma). Results: TSGs largely assort into distinct classes associated with either pan-cancer (Class I) or lineage-specific (Class II) patterns of biallelic loss, while some TSGs, mostly transcription factors, were predominantly monoallelic (Class III/IV). We discover that gene expression and co-mutation patterns indicate selection for biallelic losses in noncanonical contexts, including APC in lung and prostate adenocarcinomas. Selection for biallelic inactivation is also significantly elevated among variants of unknown significance (VUS) of several TSGs, including in KEAP1 in lung adenocarcinoma, nominating these VUS as worthy of in depth functional characterization. Patients with KEAP1 VUS also show similarly poor survival and response to chemoimmunotherapy to patients with known KEAP1 driver mutations, indicating that KEAP1 VUSs phenocopy established KEAP1 oncogenic alleles, and that zygosity, rather than variant classification, is prognostic of therapeutic response. Conclusion: TSGs vary significantly in their patterns of biallelic inactivation, and can be classified according to whether and how consistently, across cancer types, they are selected for loss of both copies. Additionally, taking into account the zygosity of TSG alteration events is often necessary to understand their phenotypic and clinical consequences, and can be useful in identifying novel driver events. Citation Format: Mark R. Zucker, Maria A. Perry, Arielle Elkrief, Anton Safonov, Rohit Thummalapalli, Samuel I. Gould, Debyani Chakravarty, Rose Brannon, Marc Ladanyi, Pedram Razavi, Mark T. Donoghue, Yonina R. Murciano-Goroff, Francisco J. Sánchez-Rivera, Yuan Chen, Ronglai Shen, Sarat Chandarlapaty, David B. Solit, Nikolaus Schultz, Michael F. Berger, Adam J. Schoenfeld, Jason Chang, Ed Reznik, Chaitanya Bandlamudi. Signatures of selection for biallelic inactivation in tumor suppressor genes across cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1202.
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Galanopoulos, Athanasios G., Stephanos Papadhimitriou, Ioannis Tsourveloudis, Evridiki Michalis, Theodoros Marinakis, Anastasia Tsakiridou, Ioanna Savvidou et al. "Deletion of Tumor Suppressor Genes (TSGS) in Patients with Myelodysplastic Syndrome (MDS)." Blood 106, n.º 11 (16 de noviembre de 2005): 4907. http://dx.doi.org/10.1182/blood.v106.11.4907.4907.
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Abstract Background: The deletion of genomic sites harboring TSGs is known to be a powerful prognostic indicator in various chronic hematologic malignancies. However, the clinical significance of TSGs loss in MDS has not been thoroughly investigated. Aims: To summarize our experience on the incidence and essential clinical correlates of TSGs deletions in MDS, providing preliminary results from the study of 27 patients. Methods: The study included 17 men and 10 women (median age 74; range 38–84 years) with a documented diagnosis of MDS. The distribution of FAB subtypes was RA in 13, RARS in 3, RAEB in 6, RAEB-T in 4 and CMML in 1 case. According to the IPSS stratification, 5 patients were characterized as “low-risk”, 16 as “intermediate-risk” (11 as INT-1 and 5 as INT-2) and 6 as “high-risk” patients. The diagnostic bone marrow smears were studied with fluorescence in-situ hybridization (FISH) for deletions of chromosome regions 9p21 (p16/p14 and p15 genes), 9q34, 12p13 (TEL gene), 13q14 (RB1 gene D13S319 locus) and 17p13 (p53 gene). Results: A deletion in at least one of the chromosome regions or loci studied was detected in 10 patients (37%). In 6 of them, more than one region locus was lost, making up a total of 20 deletions. The commonest finding was loss of the 17p13 region (5 cases; two of them homozygous), followed by 9p21 loss (5 cases; one of them homozygous). Overall, the presence of TSGs deletions was associated with complex karyotype, high IPSS score and risk of death (regardless of leukemic progression). Interestingly, deletion in at least one of the TSGs studied was found in 5 of the 17 patients presenting with normal karyotype. In 3 of these patients, the MDS progressed to acute leukemia. Two of the 5 patients died at one and six months from diagnosis of the MDS, without leukemic conversion. Summary/Conclusions: Deletions of TSGs are not uncommon in MDS. Interestingly, we have found that certain TSGs, such as the p16/p14 and p15 genes at 9p21, the loss of which is mostly involved in the initiation or progression of lymploid neoplasms, are also frequently deleted in MDS. Overall, TSGs deletion in this small group of patients is apparently associated with other adverse biological and clinical features and poor outcome. Therefore, these preliminary observations justify the expansion of the study in a larger patient cohort, in order to clarify if the loss of certain TSGs is an independent prognostic factor in MDS and, thus, may be of help in the initial diagnostic approach and risk stratification of the patients.
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Lyu, Jie, Jingyi Jessica Li, Jianzhong Su, Fanglue Peng, Yiling Elaine Chen, Xinzhou Ge y Wei Li. "DORGE: Discovery of Oncogenes and tumoR suppressor genes using Genetic and Epigenetic features". Science Advances 6, n.º 46 (noviembre de 2020): eaba6784. http://dx.doi.org/10.1126/sciadv.aba6784.
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Data-driven discovery of cancer driver genes, including tumor suppressor genes (TSGs) and oncogenes (OGs), is imperative for cancer prevention, diagnosis, and treatment. Although epigenetic alterations are important for tumor initiation and progression, most known driver genes were identified based on genetic alterations alone. Here, we developed an algorithm, DORGE (Discovery of Oncogenes and tumor suppressoR genes using Genetic and Epigenetic features), to identify TSGs and OGs by integrating comprehensive genetic and epigenetic data. DORGE identified histone modifications as strong predictors for TSGs, and it found missense mutations, super enhancers, and methylation differences as strong predictors for OGs. We extensively validated DORGE-predicted cancer driver genes using independent functional genomics data. We also found that DORGE-predicted dual-functional genes (both TSGs and OGs) are enriched at hubs in protein-protein interaction and drug-gene networks. Overall, our study has deepened the understanding of epigenetic mechanisms in tumorigenesis and revealed previously undetected cancer driver genes.
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Taneja, Pankaj, Sinan Zhu, Dejan Maglic, Eizabeth A. Fry, Robert D. Kendig y Kazushi Inoue. "Transgenic and Knockout Mice Models to Reveal the Functions of Tumor Suppressor Genes". Clinical Medicine Insights: Oncology 5 (enero de 2011): CMO.S7516. http://dx.doi.org/10.4137/cmo.s7516.
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Cancer is caused by multiple genetic alterations leading to uncontrolled cell proliferation through multiple pathways. Malignant cells arise from a variety of genetic factors, such as mutations in tumor suppressor genes (TSGs) that are involved in regulating the cell cycle, apoptosis, or cell differentiation, or maintenance of genomic integrity. Tumor suppressor mouse models are the most frequently used animal models in cancer research. The anti-tumorigenic functions of TSGs, and their role in development and differentiation, and inhibition of oncogenes are discussed. In this review, we summarize some of the important transgenic and knockout mouse models for TSGs, including Rb, p53, Ink4a/Arf, Brca1/2, and their related genes.
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Wu, Qibiao, Yahui Tian, Jian Zhang, Xinyuan Tong, Hsinyi Huang, Shuai Li, Hong Zhao et al. "In vivo CRISPR screening unveils histone demethylase UTX as an important epigenetic regulator in lung tumorigenesis". Proceedings of the National Academy of Sciences 115, n.º 17 (9 de abril de 2018): E3978—E3986. http://dx.doi.org/10.1073/pnas.1716589115.
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Lung cancer is the leading cause of cancer-related death worldwide. Inactivation of tumor suppressor genes (TSGs) promotes lung cancer malignant progression. Here, we take advantage of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated somatic gene knockout in aKrasG12D/+mouse model to identify bona fide TSGs. From individual knockout of 55 potential TSGs, we identify five genes, includingUtx,Ptip,Acp5,Acacb, andClu, whose knockout significantly promotes lung tumorigenesis. These candidate genes are frequently down-regulated in human lung cancer specimens and significantly associated with survival in patients with lung cancer. Through crossing the conditionalUtxknockout allele to theKrasG12D/+mouse model, we further find thatUtxdeletion dramatically promotes lung cancer progression. The tumor-promotive effect ofUtxknockout in vivo is mainly mediated through an increase of the EZH2 level, which up-regulates the H3K27me3 level. Moreover, theUtx-knockout lung tumors are preferentially sensitive to EZH2 inhibitor treatment. Collectively, our study provides a systematic screening of TSGs in vivo and identifies UTX as an important epigenetic regulator in lung tumorigenesis.
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Liu, Ziqiang, Juhua Huang, Ming Cao, Guiwen Jiang, Jin Hu y Qiang Chen. "Preparation of Binary Thermal Silicone Grease and Its Application in Battery Thermal Management". Materials 13, n.º 21 (26 de octubre de 2020): 4763. http://dx.doi.org/10.3390/ma13214763.
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To improve the problems of large interface thermal resistance and low heat dissipation efficiency in battery thermal management (BTM), this paper uses methyl silicone oil as the matrix, AIN, copper powder (CP), and carbon fiber (CF) as thermally conductive fillers, and acetone and stearic acid as particle surface modification components. A variety of binary thermal silicone greases (TSGs) with different compositions were prepared. Different instruments were used to test the material properties of TSGs, and a better TSG was selected to coat the interface between battery and phase change material (PCM) for battery charging and discharging experiments. Through the analysis of experimental data, it was found that among the TSGs made of three mixed fillers (AIN/CP, AIN/CF, CP/CF), the three TSGs had good thermal stability, and their thermal degradation temperature both exceeded 300 °C. As the ratio of thermally conductive filler was gradually changed from 5:1 to 1:5, the TSG containing CP/CF had higher thermal conductivity and lower volume resistivity, while the TSG containing AIN/CF had the least damage due to interface wear. The acidification treatment of thermally conductive filler can improve the adsorption and compatibility of thermally conductive particles and silicone oil, and reduce the oil separation rate of TSGs. The prepared expanded graphite (EG)/paraffin wax (PW) composite phase change material (CPCM) has a relatively large latent heat of phase change, which can effectively control the temperature of the battery, but coating TSG between the battery and the CPCM can further enhance the heat dissipation effect of the battery.
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Dashevsky, Olga, Sara Gandolfi, Olli Dufva, Ricardo De Matos Simoes, Jani Huuhtanen, Benjamin G. Barwick, Ryosuke Shirasaki et al. "Natural Killer Cells Are Active Against Myeloma, Leukemia or Lymphoma Cells with Loss of Tumor Suppressor Genes". Blood 142, Supplement 1 (28 de noviembre de 2023): 6842. http://dx.doi.org/10.1182/blood-2023-189570.
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The therapeutic targeting of tumor cells with loss of function (LOF) for tumor suppressor genes (TSGs) is challenging across cancers, including hematologic neoplasias, because pharmacological mechanisms to restore the function(s) of such genes are not readily feasible, in contrast to e.g., inhibition of oncogenic drivers. We reasoned, however, that, although LOF for TSGs leads to de-repressed growth of neoplastic hematopoietic cells, it may not necessarily protect them from immune attack. We thus explored the hypothesis that CRISPR-based loss of function of TSGs in cells from multiple myeloma (MM), leukemias or lymphoma may still be associated with substantial response to immune effector cells such as NK cells, which have the advantage to kill tumor cells across HLA barriers. We have conducted CRISPR-based studies in 7 cell lines that represent different hematologic malignancies and different levels of sensitivity to natural killer (NK) cells, namely the B-cell lymphoma (SUDHL4), precursor B cell acute lymphoblastic leukemia (NALM6), multiple myeloma (MM1.S, LP1, KMS11), chronic myeloid leukemia (K562), and acute myeloid leukemia (MOLM14). In these genome-scale or focused CRISPR screens for LOF (CRISPR-based gene editing) or gain of function (GOF, CRISPR activation), the blood cancer lines were exposed to allogeneic donor-derived NK cells (vs. control cultures without NK cells). We evaluated the performance of genes known to represent recurrent TSGs based on genomic data of patient samples or cell lines; as well as candidate TSGs, based on results from genome-scale CRISPR gene editing screens (e.g., CERES or CHRONOS scores >0.4 in multiple DepMap releases and TPM>1 [RNA-seq]) in the same cell lines as the NK cell resistance screens. These analyses sought to identify any TSGs whose LOF may potentially alter the response of blood cancer cells to NK cells. We also evaluated genes identified as top recurrent TSGs in patient samples from MM and other hematologic neoplasias (e.g., based on prior genomic studies). On aggregate, we evaluated a collection of known and recurrent TSGs (e.g., PTEN, TP53, RB1, CDKN2C, CDKN1B, TENT5C/FAM46C) as well as other, previously underappreciated candidate genes with TSG properties in hematologic neoplasias (e.g., HIF1A, DEPDC5). Perturbation of none of these genes was identified to meet criteria for association with significant resistance to allogeneic donor-derived NK cells (e.g., log2FC>1.0, at least 3-4 sgRNAs with enrichment upon CRISPR KO or depletion with CRISPR activation, p-value <0.05, enrichment rank <100, based on rank aggregation algorithm) in any of the MM, leukemia or lymphoma cell lines examined in LOF or GOF CRISPR screens for NK cell resistance. In fact, for a limited set of cases (e.g., PTEN in KMS11 cells), KO of a TSG was associated with sensitization to NK cell treatment. To probe the mechanistic basis for this lack of effect of TSG loss, we examined the molecular sequelae of CRISPR-based KO for one of these recurrent TSGs, PTEN, by performing scRNAseq using the CROP-seq platform. Pools of MM1.S and LP1 cells expressing sgRNAs targeting select hits from our CRISPR screens and also PTEN were co-cultured with NK cells for 24 h or left untreated, followed by scRNA-seq and sgRNA detection, differential gene-expression analysis. We observed in these studies that the transcriptional changes induced in MM cells by KO of PTEN included limited, if any, changes in the expression of key genes involved in regulation of NK cell responses of tumor cells, e.g., ligands for activating or inhibitor receptors in NK cells, death receptors (e.g., TRAIL, Fas) or their downstream effectors/regulators or other molecules identified from our aforementioned genome-scale and focused CRISPR LOF and GOF studies. Notably, our in-house results from studies of NK exposure of cell lines from hematologic neoplasias are concordant with results for these TSGs in CRISPR screens of non-hematological cancer cells treated with cytotoxic T-cells (e.g., 4T1 or RENCA cells; GSE149933). Overall, our observations indicate that MM, leukemia or lymphoma cells that become deficient for diverse TSGs based on CRISPR-based gene editing are equally responsive to NK cells as their TSG-proficient counterparts. NK cell-based therapies may thus be a promising approach to target TSG-deficient hematologic malignancies for which specific pharmacological therapies are not currently available.
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Hess, Corine J., Johannes Berkhof, Fedor Denkers, Gert J. Ossenkoppele, Gerrit Jan Schuurhuis y Quinten Waisfisz. "Methylation of ESR1 and Tumour Suppressor Genes Together Constitute an Independent Outcome Predictor in Acute Myeloid Leukemia." Blood 108, n.º 11 (16 de noviembre de 2006): 803. http://dx.doi.org/10.1182/blood.v108.11.803.803.
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Abstract In acute myeloid leukemia (AML) promoter methylation has been observed for the estrogen receptor (ESR1) as well as for a number of Tumor Suppressor Genes (TSGs). These individual aberrancies were suggested to be part of a general methylation defect in subsets of AML patients, rather than random events. The objective of this study was to assess whether aberrant promoter methylation of multiple genes, as observed in AML samples, are associated and whether such associations render impact on clinical outcome. By Methylation-Specific Multiplex Ligation Probe Amplification (MS-MLPA) the methylation status of 26 TSGs was determined in bone marrow samples of 119 primary AML patients and 5 control individuals. No promoter methylation was detected in any of the controls, while at least one TSG was methylated in 59/119 patients. Methylation was observed in 12 out of 26 assessed sites, most frequently for ER, CDKN2B/p15, and IGSF4 (28–36% of all patients). A substantial intra-class correlation of 0.38 existed between methylation of different TGSs. ESR1 methylation (34/119) strongly predicted concurrent methylation of TSGs, OR 7.33 (95%CI 4.13–12.99). A regression model that included both the ESR1 methylation status and the number of methylated TSGs (methylation index), showed both parameters to be independent oppositely directed predictors for overall survival (OS), HR 0.06 (95%CI 0.01–0.33; p=.001) and HR 1.92 (95%CI 1.19–3.10; p=.007), respectively. In line with this observation, a higher methylation index was found to yield a significant negative effect on patient OS in both the ESR1 methylated (ESR1+) and ESR1 unmethylated (ESR1−) subgroups. Combining ESR1 methylation status with the absence or presence of promoter methylation of other TSGs (TSG+ or TSG−); yielded 4 patient subgroups with large differences in OS in univariate analysis (p=.0001, figure 1A). In multivariate analysis that included, FLT3-status, age at diagnosis, cytogenetics and achievement of CR, the predictive impact of the 4-group division on OS was maintained, HR 2.12 (95%CI 1.04–4.29; p=.037). Moreover, the combination identified a good prognostic patient subgroup (n=15, median OS 39 month) within the intermediate cytogenetic risk group (n=54, median OS 8.3 month), figure 1B. In conclusion, concurrent methylation occurs frequent in AML and is best predicted by ESR1 methylation. Methylation of ESR1 and methylation of other TSGs represent processes with independent predictivity. When combined, they constitute a unique and powerful factor for predicting overall survival, both in the total AML population as well as within the intermediate cytogenetic risk group. Figure 1. Overall Survival based on the methylation status of ER (ER+/ER) combined with the absence or presence of methylation of TSGs (TSG+/TSG−) for the total population (A) and confined to the intermediate cytogenetic risk group (B) Figure 1. Overall Survival based on the methylation status of ER (ER+/ER) combined with the absence or presence of methylation of TSGs (TSG+/TSG−) for the total population (A) and confined to the intermediate cytogenetic risk group (B)
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Matsubara, Shin, Tomohiro Osugi, Akira Shiraishi, Azumi Wada y Honoo Satake. "Comparative analysis of transcriptomic profiles among ascidians, zebrafish, and mice: Insights from tissue-specific gene expression". PLOS ONE 16, n.º 9 (24 de septiembre de 2021): e0254308. http://dx.doi.org/10.1371/journal.pone.0254308.
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Tissue/organ-specific genes (TSGs) are important not only for understanding organ development and function, but also for investigating the evolutionary lineages of organs in animals. Here, we investigate the TSGs of 9 adult tissues of an ascidian, Ciona intestinalis Type A (Ciona robusta), which lies in the important position of being the sister group of vertebrates. RNA-seq and qRT-PCR identified the Ciona TSGs in each tissue, and BLAST searches identified their homologs in zebrafish and mice. Tissue distributions of the vertebrate homologs were analyzed and clustered using public RNA-seq data for 12 zebrafish and 30 mouse tissues. Among the vertebrate homologs of the Ciona TSGs in the neural complex, 48% and 63% showed high expression in the zebrafish and mouse brain, respectively, suggesting that the central nervous system is evolutionarily conserved in chordates. In contrast, vertebrate homologs of Ciona TSGs in the ovary, pharynx, and intestine were not consistently highly expressed in the corresponding tissues of vertebrates, suggesting that these organs have evolved in Ciona-specific lineages. Intriguingly, more TSG homologs of the Ciona stomach were highly expressed in the vertebrate liver (17–29%) and intestine (22–33%) than in the mouse stomach (5%). Expression profiles for these genes suggest that the biological roles of the Ciona stomach are distinct from those of their vertebrate counterparts. Collectively, Ciona tissues were categorized into 3 groups: i) high similarity to the corresponding vertebrate tissues (neural complex and heart), ii) low similarity to the corresponding vertebrate tissues (ovary, pharynx, and intestine), and iii) low similarity to the corresponding vertebrate tissues, but high similarity to other vertebrate tissues (stomach, endostyle, and siphons). The present study provides transcriptomic catalogs of adult ascidian tissues and significant insights into the evolutionary lineages of the brain, heart, and digestive tract of chordates.
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Azzoli, Christopher G., Alexander Edward Dela Cruz Drilon, Hirofumi Sugita, Camelia S. Sima, Eric Huang, Peter V. Danenberg, Mark G. Kris y Valerie W. Rusch. "Prospective study of tumor suppressor gene (TSG) methylation as a prognostic biomarker in surgically resected non-small cell lung cancer (NSCLC)." Journal of Clinical Oncology 30, n.º 15_suppl (20 de mayo de 2012): 7066. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.7066.
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7066 Background: In the New England Journal of Medicine, Brock et al. (2008) published a nested case-control study which tested the association between early recurrence of NSCLC after surgical resection, and TSG promoter methylation in tumor and lymph nodes detected by methylation-specific PCR (MSP). They reported that promoter methylation of the TSGs p16, CDH13, RASSF1A, and APC was significantly associated with early recurrence in 51 patients with stage I NSCLC compared to matched patients without early recurrence. We attempted to confirm these findings. Methods: In a prospective study, fresh frozen tumor tissue was acquired after surgical resection in 107 patients with stage I-IIIA NSCLC between 2003-2008. The promoter methylation status of the same 4 genes examined by Brock, et al (p16, CDH13, RASSF1A, APC), as well as 6 additional TSGs (MGMT, WIF-1, METH-2, GSTP1, SOCS3, DAPK) were assessed in the tumor tissue using quantitative MSP (MethyLight assay), with any amount of methylation scored as positive. Methylation status was correlated with clinical features, pathologic stage, disease-free survival (DFS), and overall survival (OS). Results: No significant associations were observed between promoter methylation of individual TSGs and DFS. No significant associations were observed between the number of methylated TSGs and DFS, or OS. Increased RASSF1A methylation was observed in poorly-differentiated and undifferentiated tumors compared to tumors that were well- or moderately-differentiated (p=0.031). Increased WIF-1 methylation and GSTP1 methylation were associated with increasing T (p=0.01) and N stage (p=0.028), respectively. Squamous cell carcinomas (SQCCs) were characterized by increased p16 methylation (p=0.0314) and decreased APC methylation (p=0.0146) compared to tumors of non-SQCC histologies. Conclusions: In this prospective study, we did not confirm that the promoter methylation of p16, CDH13, RASSF1A, and APC, or 6 other TSGs, was prognostic for early recurrence in surgically resected NSCLC.
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Daly, Julie-Anne, Sally-Anne Mortlock, Rosanne M. Taylor y Peter Williamson. "Cluster Analysis of Tumor Suppressor Genes in Canine Leukocytes Identifies Activation State". Bioinformatics and Biology Insights 9s2 (enero de 2015): BBI.S30523. http://dx.doi.org/10.4137/bbi.s30523.
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Cells of the immune system undergo activation and subsequent proliferation in the normal course of an immune response. Infrequently, the molecular and cellular events that underlie the mechanisms of proliferation are dysregulated and may lead to oncogenesis, leading to tumor formation. The most common forms of immunological cancers are lymphomas, which in dogs account for 8%-20% of all cancers, affecting up to 1.2% of the dog population. Key genes involved in negatively regulating proliferation of lymphocytes include a group classified as tumor suppressor genes (TSGs). These genes are also known to be associated with progression of lymphoma in humans, mice, and dogs and are potential candidates for pathological grading and diagnosis. The aim of the present study was to analyze TSG profiles in stimulated leukocytes from dogs to identify genes that discriminate an activated phenotype. A total of 554 TSGs and three gene set collections were analyzed from microarray data. Cluster analysis of three subsets of genes discriminated between stimulated and unstimulated cells. These included 20 most upregulated and downregulated TSGs, TSG in hallmark gene sets significantly enriched in active cells, and a selection of candidate TSGs, p15 ( CDKN2B), p18 ( CDKN2C), p19 ( CDKN1A), p21 ( CDKN2A), p27 ( CDKN1B), and p53 ( TP53) in the third set. Analysis of two subsets suggested that these genes or a subset of these genes may be used as a specialized PCR set for additional analysis.
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Wee, YongKiat, Yining Liu y Min Zhao. "Identification of consistent post-translational regulatory triplets related to oncogenic and tumour suppressive modulators in childhood acute lymphoblastic leukemia". PeerJ 9 (14 de julio de 2021): e11803. http://dx.doi.org/10.7717/peerj.11803.
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Background Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer. It can be caused by mutations that turn on oncogenes or turn off tumour suppressor genes. For instance, changes in certain genes including Rb and p53 are common in ALL cells. Oncogenes and TSGs may serve as a modulator gene to regulate the gene expression level via their respective target genes. To investigate the regulatory relationship between oncogenes, tumour suppressor genes and transcription factors at the post translational level in childhood ALL, we performed an integrative network analysis on the gene regulation in the post-translational level for childhood ALL based on many publicly available cancer gene expression data including TARGET and GEO database. Methods We collected 259 childhood ALL-related genes from the latest online leukemia database, Leukemia Gene Literature Database. These 259 genes were selected from a comprehensive systematic literature with experimental evidences. The identified and curated genes were also associated with patient survival cases and we incorporated this pediatric ALL-related gene list into our analysis. We extracted the known human TFs from the TRRUST database. Among 259 childhood ALL-related genes, 101 unique regulators were mapped to the list of oncogene and tumour suppressor genes (TSGs) from the ONGene and the TSGene databases, and these included 74 TSGs, 62 oncogenes and 46 TF genes. Results The resulted regulation was presented as a hierarchical regulatory network with transcription factors (TFs) as intermediate regulators connecting the top modulators (oncogene and TSGs) to the common target genes. Cross-validation was applied to the results from the TARGET dataset by identifying the consistent regulatory motifs based on three independent ALL expression datasets. A three-layer regulatory network of consistent positive modulators in childhood ALL was constructed in which 74 modulators (40 oncogenes, 34 TSGs) are considered as the most important regulators. The middle layer and the bottom layer contain 34 TFs and 176 target genes, respectively. Oncogenes mostly participated in positive regulation of gene expression and the transcription process of RNA II polymerase, while TSGs were mainly involved in the negative regulation of gene expression. In addition, the oncogene-specific targets were enriched with regulators of the MAPK cascade while tumour suppressor-specific targets were associated with cell death. Conclusion The results revealed that oncogenes and TSGs possess a different functional regulatory pattern with regard to not only their biological functions but also their specific target genes in childhood ALL cancer progression. Taken together, our findings could contribute to a better understanding of the important regulatory mechanisms and this method could be used to analyse the targeted genes at the post-translational level in childhood ALL through integrative network analysis.
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Saha, Abhik, Hem C. Jha, Santosh K. Upadhyay y Erle S. Robertson. "Epigenetic silencing of tumor suppressor genes during in vitro Epstein–Barr virus infection". Proceedings of the National Academy of Sciences 112, n.º 37 (31 de agosto de 2015): E5199—E5207. http://dx.doi.org/10.1073/pnas.1503806112.
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DNA-methylation at CpG islands is one of the prevalent epigenetic alterations regulating gene-expression patterns in mammalian cells. Hypo- or hypermethylation-mediated oncogene activation, or tumor suppressor gene (TSG) silencing mechanisms, widely contribute to the development of multiple human cancers. Furthermore, oncogenic viruses, including Epstein–Barr virus (EBV)-associated human cancers, were also shown to be influenced by epigenetic modifications on the viral and cellular genomes in the infected cells. We investigated EBV infection of resting B lymphocytes, which leads to continuously proliferating lymphoblastoid cell lines through examination of the expression pattern of a comprehensive panel of TSGs and the epigenetic modifications, particularly methylation of their regulatory sequences. EBV infection of primary B lymphocytes resulted in global transcriptional repression of TSGs through engagement of hypermethylation. Therefore, CpG methylation profiles of TSGs may be used as a prognostic marker as well as development of potential therapeutic strategies for controlling acute infection and EBV-associated B-cell lymphomas.
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Kang, Sangguk, Dong-Han Kim y Jaeseok Lee. "The Role of a Community-Based Leisure Program for Older Adults’ Leisure-Time Physical Activity: A Focus on the Social–Ecological Model". Sustainability 15, n.º 20 (13 de octubre de 2023): 14851. http://dx.doi.org/10.3390/su152014851.
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Objective: The purpose of this study was to identify how a community-based leisure program (CBLP) interacted with older adults’ leisure-time physical activity (LTPA) based on the social–ecological model. Method: Individual semi-structured interviews were completed with 19 older adults who participated in the Tennessee senior games (TSGs). Results: As a type of CBLP and an organizational factor, the TSGs were highly intertwined with intrapersonal factors, interpersonal factors, and community factors that enabled the older adults to easily access and enhance their LTPA. Intrapersonal factors, socioeconomic status, perceived functional ability, and three main motivation factors (i.e., physical health, positive feelings, and competition) emerged for TSG participation. As interpersonal factors, the majority of the older adults encountered the TSGs for the first time through their family, friends, coaches, doctors, or team colleagues. Conclusion: Participants were encouraged to maintain LTPA by interactions with other TSG participants. Community factors provided places and volunteers for a successful CBLP with advertisements (i.e., TV, board at gym).
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Kim, Tae-Oh, Yu Kyeong Han y Joo Mi Yi. "Hypermethylated promoters of tumor suppressor genes were identified in Crohn’s disease patients". Intestinal Research 18, n.º 3 (30 de julio de 2020): 297–305. http://dx.doi.org/10.5217/ir.2019.00105.
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Background/Aims: Overwhelming evidence suggests that inflammatory bowel disease (IBD) is caused by a complicated interplay between the multiple genes and abnormal epigenetic regulation in response to environmental factors. It is becoming apparent that epigenetic factors are significantly associated with the development of the disease. DNA methylation remains the most studied epigenetic modification, and hypermethylation of gene promoters is associated with gene silencing.Methods: DNA methylation alterations may contribute to the many complex diseases development by regulating the interplay between external and internal environmental factors and gene transcriptional expression. In this study, we used 15 tumor suppressor genes (TSGs), originally identified in colon cancer, to detect promoter methylation in patients with Crohn’s disease (CD). Methylation specific polymerase chain reaction and bisulfite sequencing analyses were performed to assess methylation level of TSGs in CD patients.Results: We found 6 TSGs (<i>sFRP1, sFRP2, sFRP5, TFPI2, Sox17</i>, and <i>GATA4</i>) are robustly hypermethylated in CD patient samples. Bisulfite sequencing analysis confirmed the methylation levels of the <i>sFRP1, sFRP2, sFRP5, TFPI2, Sox17</i>, and <i>GATA4</i> promoters in the representative CD patient samples.Conclusions: In this study, the promoter hypermethylation of the TSGs observed indicates that CD exhibits specific DNA methylation signatures with potential clinical applications for the noninvasive diagnosis of IBD and the prognosis for patients with IBD.
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Pan, Xiangchun, Jiali Cai, Yifei Wang, Dantong Xu, Yao Jiang, Wentao Gong, Yuhan Tian et al. "Expression Profile of Housekeeping Genes and Tissue-Specific Genes in Multiple Tissues of Pigs". Animals 12, n.º 24 (15 de diciembre de 2022): 3539. http://dx.doi.org/10.3390/ani12243539.
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Pigs have become an ideal model system for human disease research and development and an important farm animal that provides a valuable source of nutrition. To profile the all-sided gene expression and their biological functions across multiple tissues, we conducted a comprehensive analysis of gene expression on a large scale around the side of housekeeping genes (HKGs), tissue specific genes (TSGs), and the co-expressed genes in 14 various tissues. In this study, we identified 2351 HKGs and 3018 TSGs across tissues, among which 4 HKGs (COX1, UBB, OAZ1/NPFF) exhibited low variation and high expression levels, and 31 particular TSGs (e.g., PDC, FKBP6, STAT2, and COL1A1) were exclusively expressed in several tissues, including endocrine brain, ovaries, livers, backfat, jejunum, kidneys, lungs, and longissimus dorsi muscles. We also obtained 17 modules with 230 hub genes (HUBGs) by weighted gene co-expression network analysis. On the other hand, HKGs functions were enriched in the signaling pathways of the ribosome, spliceosome, thermogenesis, oxidative phosphorylation, and nucleocytoplasmic transport, which have been highly suggested to involve in the basic biological tissue activities. While TSGs were highly enriched in the signaling pathways that were involved in specific physiological processes, such as the ovarian steroidogenesis pathway in ovaries and the renin-angiotensin system pathway in kidneys. Collectively, these stable, specifical, and co-expressed genes provided useful information for the investigation of the molecular mechanism for an understanding of the genetic and biological processes of complex traits in pigs.
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Tejada-Martinez, Daniela, João Pedro de Magalhães y Juan C. Opazo. "Positive selection and gene duplications in tumour suppressor genes reveal clues about how cetaceans resist cancer". Proceedings of the Royal Society B: Biological Sciences 288, n.º 1945 (24 de febrero de 2021): 20202592. http://dx.doi.org/10.1098/rspb.2020.2592.
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Cetaceans are the longest-living species of mammals and the largest in the history of the planet. They have developed mechanisms against diseases such cancer, although the underlying molecular bases of these remain unknown. The goal of this study was to investigate the role of natural selection in the evolution of 1077 tumour suppressor genes (TSGs) in cetaceans. We used a comparative genomic approach to analyse two sources of molecular variation in the form of d N / d S rates and gene copy number variation. We found a signal of positive selection in the ancestor of cetaceans within the CXCR2 gene, an important regulator of DNA damage, tumour dissemination and immune system. Further, in the ancestor of baleen whales, we found six genes exhibiting positive selection relating to diseases such as breast carcinoma, lung neoplasm ( ADAMTS8 ) and leukaemia ( ANXA1 ). The TSGs turnover rate (gene gain and loss) was almost 2.4-fold higher in cetaceans when compared with other mammals, and notably even faster in baleen whales. The molecular variants in TSGs found in baleen whales, combined with the faster gene turnover rate, could have favoured the evolution of their particular traits of anti-cancer resistance, gigantism and longevity. Additionally, we report 71 genes with duplications, of which 11 genes are linked to longevity (e.g. NOTCH3 and SIK1 ) and are important regulators of senescence, cell proliferation and metabolism. Overall, these results provide evolutionary evidence that natural selection in TSGs could act on species with large body sizes and extended lifespan, providing novel insights into the genetic basis of disease resistance.
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Blanchard, Thomas G., Rena Lapidus, Vivekjyoti Banerjee, Andrea C. Bafford, Steven J. Czinn, Hafiz Ahmed y Aditi Banerjee. "Upregulation of RASSF1A in Colon Cancer by Suppression of Angiogenesis Signaling and Akt Activation". Cellular Physiology and Biochemistry 48, n.º 3 (2018): 1259–73. http://dx.doi.org/10.1159/000492012.
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Background/Aims: Silencing of tumor suppressor genes (TSGs) and promotion of angiogenesis are associated with tumor development and metastasis. However, little is known if angiogenic molecules directly control TSGs and vice versa. Methods: A regulatory link between angiogenesis and down regulation of TSGs was evaluated using an anti-cancer agent, andrographolide (AGP) in cancer cells, mouse xenograft tissues and patient derived organoids through gene/protein expression, gene silencing, and immunohistochemical analyses. Results: AGP treatment demonstrated significant expression of RASSF1A and PTEN TSGs in colon cancer and other cancer cells, mouse tissues and organoids. Depletion of RASSF1A with siRNA limited cyclin D1 and BAX expression. SiRNA depletion of PTEN, upstream regulator of RASSF1A resulted in a 50% reduction in RASSF1A expression. Histopathological analysis of the AGP treated tumor sections showed significant reduction in vessel size, microvascular density and tumor mitotic index suggesting suppression of angiogenesis. This was corroborated by protein analysis demonstrating significant reductions in angiogenesis signaling pathway molecules VEGF165, FOXM1, and pAkt, but significant elevation of the endogenous angiogenesis inhibitor Tsp-2. Treatment of cells with exogenous VEGF prevented the suppression of angiogenesis signaling by AGP, resulting in sustained expression of pAkt, an upstream down-regulator of RASSF1A. RASSF1A expression remained low in VEGF treated cells despite the addition of AGP. Conclusion: Our results demonstrate for the first time that AGP induces RASSF1A expression in colon cancer cells and is dependent on angiogenesis signaling events. Therefore, our research may facilitate novel therapeutic options for advanced colon cancer therapy.
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Rajabi, Sadegh, Catherine Alix-Panabières, Arshia Sharbatdar Alaei, Raziyeh Abooshahab, Heewa Shakib y Mohammad Reza Ashrafi. "Looking at Thyroid Cancer from the Tumor-Suppressor Genes Point of View". Cancers 14, n.º 10 (17 de mayo de 2022): 2461. http://dx.doi.org/10.3390/cancers14102461.
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Thyroid cancer is the most frequent endocrine malignancy and accounts for approximately 1% of all diagnosed cancers. A variety of mechanisms are involved in the transformation of a normal tissue into a malignant one. Loss of tumor-suppressor gene (TSG) function is one of these mechanisms. The normal functions of TSGs include cell proliferation and differentiation control, genomic integrity maintenance, DNA damage repair, and signaling pathway regulation. TSGs are generally classified into three subclasses: (i) gatekeepers that encode proteins involved in cell cycle and apoptosis control; (ii) caretakers that produce proteins implicated in the genomic stability maintenance; and (iii) landscapers that, when mutated, create a suitable environment for malignant cell growth. Several possible mechanisms have been implicated in TSG inactivation. Reviewing the various TSG alteration types detected in thyroid cancers may help researchers to better understand the TSG defects implicated in the development/progression of this cancer type and to find potential targets for prognostic, predictive, diagnostic, and therapeutic purposes. Hence, the main purposes of this review article are to describe the various TSG inactivation mechanisms and alterations in human thyroid cancer, and the current therapeutic options for targeting TSGs in thyroid cancer.
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Verma, Prince, Court K. M. Waterbury y Elizabeth M. Duncan. "Set1 Targets Genes with Essential Identity and Tumor-Suppressing Functions in Planarian Stem Cells". Genes 12, n.º 8 (29 de julio de 2021): 1182. http://dx.doi.org/10.3390/genes12081182.
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Tumor suppressor genes (TSGs) are essential for normal cellular function in multicellular organisms, but many TSGs and tumor-suppressing mechanisms remain unknown. Planarian flatworms exhibit particularly robust tumor suppression, yet the specific mechanisms underlying this trait remain unclear. Here, we analyze histone H3 lysine 4 trimethylation (H3K4me3) signal across the planarian genome to determine if the broad H3K4me3 chromatin signature that marks essential cell identity genes and TSGs in mammalian cells is conserved in this valuable model of in vivo stem cell function. We find that this signature is indeed conserved on the planarian genome and that the lysine methyltransferase Set1 is largely responsible for creating it at both cell identity and putative TSG loci. In addition, we show that depletion of set1 in planarians induces stem cell phenotypes that suggest loss of TSG function, including hyperproliferation and an abnormal DNA damage response (DDR). Importantly, this work establishes that Set1 targets specific gene loci in planarian stem cells and marks them with a conserved chromatin signature. Moreover, our data strongly suggest that Set1 activity at these genes has important functional consequences both during normal homeostasis and in response to genotoxic stress.
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Pramodh, Sreepoorna, Ritu Raina, Arif Hussain, Sali Abubaker Bagabir, Shafiul Haque, Syed Tasleem Raza, Mohammad Rehan Ajmal, Shalini Behl y Deepika Bhagavatula. "Luteolin Causes 5′CpG Demethylation of the Promoters of TSGs and Modulates the Aberrant Histone Modifications, Restoring the Expression of TSGs in Human Cancer Cells". International Journal of Molecular Sciences 23, n.º 7 (6 de abril de 2022): 4067. http://dx.doi.org/10.3390/ijms23074067.
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Cancer progression is linked to abnormal epigenetic alterations such as DNA methylation and histone modifications. Since epigenetic alterations, unlike genetic changes, are heritable and reversible, they have been considered as interesting targets for cancer prevention and therapy by dietary compounds such as luteolin. In this study, epigenetic modulatory behaviour of luteolin was analysed on HeLa cells. Various assays including colony forming and migration assays, followed by biochemical assays of epigenetic enzymes including DNA methyltransferase, histone methyl transferase, histone acetyl transferase, and histone deacetylases assays were performed. Furthermore, global DNA methylation and methylation-specific PCR for examining the methylation status of CpG promoters of various tumour suppressor genes (TSGs) and the expression of these TSGs at transcript and protein level were performed. It was observed that luteolin inhibited migration and colony formation in HeLa cells. It also modulated DNA methylation at promoters of TSGs and the enzymatic activity of DNMT, HDAC, HMT, and HAT and reduced the global DNA methylation. Decrease in methylation resulted in the reactivation of silenced tumour suppressor genes including FHIT, DAPK1, PTEN, CDH1, SOCS1, TIMPS, VHL, TP53, TP73, etc. Hence, luteolin-targeted epigenetic alterations provide a promising approach for cancer prevention and intervention.
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Liang, Ying, Qi Lu, Wei Li, Dapeng Zhang, Fanglin Zhang, Qingping Zou, Lu Chen et al. "Reactivation of tumour suppressor in breast cancer by enhancer switching through NamiRNA network". Nucleic Acids Research 49, n.º 15 (30 de julio de 2021): 8556–72. http://dx.doi.org/10.1093/nar/gkab626.
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Abstract Dysfunction of Tumour Suppressor Genes (TSGs) is a common feature in carcinogenesis. Epigenetic abnormalities including DNA hypermethylation or aberrant histone modifications in promoter regions have been described for interpreting TSG inactivation. However, in many instances, how TSGs are silenced in tumours are largely unknown. Given that miRNA with low expression in tumours is another recognized signature, we hypothesize that low expression of miRNA may reduce the activity of TSG related enhancers and further lead to inactivation of TSG during cancer development. Here, we reported that low expression of miRNA in cancer as a recognized signature leads to loss of function of TSGs in breast cancer. In 157 paired breast cancer and adjacent normal samples, tumour suppressor gene GPER1 and miR-339 are both downregulated in Luminal A/B and Triple Negative Breast Cancer subtypes. Mechanistic investigations revealed that miR-339 upregulates GPER1 expression in breast cancer cells by switching on the GPER1 enhancer, which can be blocked by enhancer deletion through the CRISPR/Cas9 system. Collectively, our findings reveal novel mechanistic insights into TSG dysfunction in cancer development, and provide evidence that reactivation of TSG by enhancer switching may be a promising alternative strategy for clinical breast cancer treatment.
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Carmena, Ana. "The Case of the Scribble Polarity Module in Asymmetric Neuroblast Division in Development and Tumorigenesis". International Journal of Molecular Sciences 21, n.º 8 (20 de abril de 2020): 2865. http://dx.doi.org/10.3390/ijms21082865.
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The Scribble polarity module is composed by Scribble (Scrib), Discs large 1 (Dlg1) and Lethal (2) giant larvae (L(2)gl), a group of highly conserved neoplastic tumor suppressor genes (TSGs) from flies to humans. Even though the Scribble module has been profusely studied in epithelial cell polarity, the number of tissues and processes in which it is involved is increasingly growing. Here we discuss the role of the Scribble module in the asymmetric division of Drosophila neuroblasts (NBs), as well as the underlying mechanisms by which those TSGs act in this process. Finally, we also describe what we know about the consequences of mutating these genes in impairing the process of asymmetric NB division and promoting tumor-like overgrowth.
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Firestone, Allison R., Rebecca A. Cruz y Janelle E. Rodl. "Teacher Study Groups: An Integrative Literature Synthesis". Review of Educational Research 90, n.º 5 (4 de julio de 2020): 675–709. http://dx.doi.org/10.3102/0034654320938128.
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Until recently, existing research on teacher professional development (PD) has largely relied on teacher perceptions and self-reports to evaluate effectiveness. Though more current research has used a diverse array of designs and methodologies to examine impact on teacher knowledge, practice, and student learning, uncertainty regarding the effectiveness of various PD models remains, particularly for these nonperceptive variables. There has been a call in the field to apply a consistent conceptual framework in order to identify critical mechanisms underlying effective models and to support improved theorizing about teaching and learning. Thus, we present an integrated literature synthesis of one collaborative model of PD, teacher study groups (TSGs), in an effort to make sense of the relatively rich body of research that has been performed on this model. We identified 32 studies that examined TSGs’ impact on teacher and student outcomes and synthesized this research using Desimone’s five-factor conceptual framework, which is being increasingly applied across the field. Findings suggest that TSGs are an effective PD model and that there are components of the model not accounted for in the five-factor framework that affect teacher outcomes and student learning. We conclude with a discussion of implications, including limitations of the five-factor framework and ideas for further refinement that situate PD in a vast empirical landscape.
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Kashima, Hajime, Daniel Veronese-Paniagua, Anthony Fischer, Blair Madison y Deborah Rubin. "A new CRISPR mediated intestinal tumor mouse model targeting four canonical tumor suppressor genes." Journal of Clinical Oncology 38, n.º 15_suppl (20 de mayo de 2020): e16064-e16064. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16064.
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e16064 Background: Mouse models of intestinal tumorigenesis have been developed and many of them involve mutations in the Apc gene. However, human intestinal tumors contain multiple additional sporadic mutations in tumor suppressor genes (TSGs). Our goal is to develop a novel mouse model of intestinal tumorigenesis that can recapitulate the natural history of mutations in diverse stages of tumor development. Methods: We used multiple guide RNAs to achieve random mutations in the canonical TSGs, Apc, Pten, Smad4, and Tp53. We generated transgenic (PPAS) mice that constitutively express the appropriate guide RNAs. Moreover, we achieved inducible Cas9 expression in icCas9N mice intestine using the Villin promoter to drive both a doxycycline-dependent activator and a doxycycline-inactivated repressor. We fed the doxycycline chow to PPAS:icCas9 double transgenic mice from the age of 6 to 8 weeks, and harvested intestine at 12 weeks. Results: We examined seven PPAS;icCas9 mice, and detected intestinal tumors in all the mice. Two mice had small intestinal tumor, three mice had colonic tumor, and two mice had tumors in both small and large intestine. The average number of tumors were 0.86, 1.57, 2.43 in small intestine, colon, and both respectively. We analyzed mutations in 11 tumors in 6 mice. The mutation patterns of Apc, Pten, Smad4 and Tp53 in tumors shared three distinct patterns. One was characterized by mutations in all four TSGs (n = 9). The second showed mutation in APC and Smad4 and Pten (n = 1). The third showed mutation only in Tp53 (n = 1). Normal intestine and colon in PPAS:icCas9 mice had no mutations. Conclusions: This model provides a powerful platform for modeling intestinal tumorigenesis driven by the canonical signaling pathway which are commonly dysregulated in colon cancer. This model provides a means for rapid development of intestinal tumors in mice, enabling an investigation of the relationship between novel candidate regulators of tumorigenesis and the canonical signaling pathways regulated by these four common TSGs. [Table: see text]
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Sundaram, Madhumitha Kedhari, Sreepoorna Unni, Pallavi Somvanshi, Tulika Bhardwaj, Raju K. Mandal, Arif Hussain y Shafiul Haque. "Genistein Modulates Signaling Pathways and Targets Several Epigenetic Markers in HeLa Cells". Genes 10, n.º 12 (21 de noviembre de 2019): 955. http://dx.doi.org/10.3390/genes10120955.
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Background: Several epigenetic changes are responsible for transcriptional alterations of signaling pathways and tumour suppressor genes (TSGs) contributing to carcinogenesis. This study was aimed to examine the effect of the phytochemical, genistein on various molecular targets in HeLa cells. Methods: Quantitative PCR was used to analyze the expression of various molecular targets. Biochemical assays were employed to study the epigenetic enzymes. To correlate the transcriptional status of the selected TSGs and epigenetic modulation, their promoter 5’CpG methylation levels were evaluated by quantitative methylation array followed by methylation specific restriction digestion. Results: The expression of several genes involved in the cell cycle regulation, migration, inflammation, phosphatidylinositol 3-kinase (PI3K) and mitogen activated kinase-like protein (MAPK) pathway were found to be modulated including CCNB1, TWIST1, MMP14, TERT, AKT1, PTPRR, FOS and IL1A. Genistein modulated the expression of DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histone methyltransferases (HMTs), demethylases, and histone phosphorylases. Furthermore, genistein decreased the activity of DNMTs, HDACs, and HMTs and reduced global DNA methylation levels. Promoter methylation of several TSGs, including FHIT, RUNX3, CDH1, PTEN, and SOC51, was lowered with corresponding transcriptional increase. Network analysis indicated similar effect of genistein. Conclusion: This study presents a comprehensive mechanism of action of genistein showcasing effective epigenetic modulation and widespread transcriptional changes resulting in restoration of tumour suppressor gene expression. This study corroborates the development of genistein as a candidate for anti-cancer therapy.
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Luchoro-Parrilla, Rafael, Pere Lavega-Burgués y Miguel Pic. "Teaching Sustainability through Traditional Sporting Games". Sustainability 16, n.º 13 (28 de junio de 2024): 5510. http://dx.doi.org/10.3390/su16135510.
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Traditional sports games (TSGs), deeply rooted in local culture, serve as valuable resources for educating in sustainable development, aligning with guidelines set forth by international resolutions such as the Agenda 2030. This study investigated how ethnomotor variables in the educational use of TSGs with objects influenced emotional well-being and the acquisition of significant and contextualised physical and social sustainability learning involving various educational agents. The study adopted a qualitative and inductive approach centred on an ethnomotor intervention to promote sustainable learning within and beyond the educational setting. A total of 226 primary school students aged between 11 and 12 from seven primary education centres in the Canary Islands, Spain participated. Seven intervention sessions were conducted, including out-of-school activities involving family members and in-school activities with the collaboration of teaching staff and a specialised researcher. Various data collection instruments were employed (field notes, questionnaires, and interviews). A content analysis of qualitative data was conducted and subsequently transformed into quantitative data. For statistical analyses of these data, multidimensional frequency areas, crosstab (Pearson’s chi-square), associated effect size (Cramer’s V), and decision trees were utilised. This research discusses the relevance of TSGs as tools for promoting physically and socially sustainable learning. Furthermore, the role of various educational agents, including family members, teachers, and teacher-researchers, in developing these experiences is highlighted. The findings also highlight emotional well-being (psychosocial and socio-emotional affectivity) as a key aspect in the process of meaningful and contextualised sustainable learning.
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Dahl, Edgar, Sophia Villwock, Peter Habenberger, Axel Choidas, Michael Rose y Bert M. Klebl. "White Paper: Mimetics of Class 2 Tumor Suppressor Proteins as Novel Drug Candidates for Personalized Cancer Therapy". Cancers 14, n.º 18 (9 de septiembre de 2022): 4386. http://dx.doi.org/10.3390/cancers14184386.
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The aim of our proposed concept is to find new target structures for combating cancers with unmet medical needs. This, unfortunately, still applies to the majority of the clinically most relevant tumor entities such as, for example, liver cancer, pancreatic cancer, and many others. Current target structures almost all belong to the class of oncogenic proteins caused by tumor-specific genetic alterations, such as activating mutations, gene fusions, or gene amplifications, often referred to as cancer “driver alterations” or just “drivers.” However, restoring the lost function of tumor suppressor genes (TSGs) could also be a valid approach to treating cancer. TSG-derived proteins are usually considered as control systems of cells against oncogenic properties; thus, they represent the brakes in the “car-of-life.” Restoring these tumor-defective brakes by gene therapy has not been successful so far, with a few exceptions. It can be assumed that most TSGs are not being inactivated by genetic alteration (class 1 TSGs) but rather by epigenetic silencing (class 2 TSGs or short “C2TSGs”). Reactivation of C2TSGs in cancer therapy is being addressed by the use of DNA demethylating agents and histone deacetylase inhibitors which act on the whole cancer cell genome. These epigenetic therapies have neither been particularly successful, probably because they are “shotgun” approaches that, although acting on C2TSGs, may also reactivate epigenetically silenced oncogenic sequences in the genome. Thus, new strategies are needed to exploit the therapeutic potential of C2TSGs, which have also been named DNA methylation cancer driver genes or “DNAme drivers” recently. Here we present a concept for a new translational and therapeutic approach that focuses on the phenotypic imitation (“mimesis”) of proteins encoded by highly disease-relevant C2TSGs/DNAme drivers. Molecular knowledge on C2TSGs is used in two complementary approaches having the translational concept of defining mimetic drugs in common: First, a concept is presented how truncated and/or genetically engineered C2TSG proteins, consisting solely of domains with defined tumor suppressive function can be developed as biologicals. Second, a method is described for identifying small molecules that can mimic the effect of the C2TSG protein lost in the cancer cell. Both approaches should open up a new, previously untapped discovery space for anticancer drugs.
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Sundaram, Madhumitha Kedhari, Mohammad Zeeshan Ansari, Abdullah Al Mutery, Maryam Ashraf, Reem Nasab, Sheethal Rai, Naushad Rais y Arif Hussain. "Genistein Induces Alterations of Epigenetic Modulatory Signatures in Human Cervical Cancer Cells". Anti-Cancer Agents in Medicinal Chemistry 18, n.º 3 (4 de junio de 2018): 412–21. http://dx.doi.org/10.2174/1871520617666170918142114.
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Introduction: Epidemiological studies indicate that diet rich in fruits and vegetables is associated with decreased cancer risk thereby indicating that dietary polyphenols can be potential chemo-preventive agents. The reversible nature of epigenetic modifications makes them a favorable target for cancer prevention. Polyphenols have been shown to reverse aberrant epigenetic patterns by targeting the regulatory enzymes, DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). In vitro and in silico studies of DNMTs and HDACs were planned to examine genistein’s role as a natural epigenetic modifier in human cervical cancer cells, HeLa. Methods: Expression of the tumour suppressor genes (TSGs) [MGMT, RARβ, p21, E-cadherin, DAPK1] as well the methylation status of their promoters were examined alongwith the activity levels of DNMT and HDAC enzymes after treatment with genistein. Expression of DNMTs and HDACs was also studied. In-silico studies were performed to determine the interaction of genistein with DNMTs and HDACs. Results: Genistein treatment significantly reduced the expression and enzymatic activity of both DNMTs and HDACs in a time-dependent way. Molecular modeling data suggest that genistein can interact with various members of DNMT and HDAC families and support genistein mediated inhibition of their activity. Timedependent exposure of genistein reversed the promoter region methylation of the TSGs and re-established their expression. Conclusions: In this study, we find that genistein is able to reinstate the expression of the TSGs studied by inhibiting the action of DNMTs and HDACs. This shows that genistein could be an important arsenal in the development of epigenetic based cancer therapy.
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Starostik, Petr, Axel Greiner, Anja Schultz, Andreas Zettl, Katharina Peters, Andreas Rosenwald, Mariele Kolve y Hans Konrad Müller-Hermelink. "Genetic aberrations common in gastric high-grade large B-cell lymphoma". Blood 95, n.º 4 (15 de febrero de 2000): 1180–87. http://dx.doi.org/10.1182/blood.v95.4.1180.004k14_1180_1187.
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Genetic aberrations associated with the development of extranodal high-grade large B-cell lymphoma originating in the stomach have not been fully identified yet. We analyzed 31 such lymphomas using 73 microsatellite markers for allelic imbalance and microsatellite instability. The highest frequency (42%) of loss of heterozygosity (LOH) was found on the long arm of chromosome 6. We identified 2 LOH hot spots on 6q21-22.1 and 6q23.3-25, flanked by markers D6S246-D6S261 and D6S310-D6S441, respectively, containing putative tumor suppressor genes (TSGs). These 6q aberrations were found to be the sole allelic imbalance in 1 patient only; they were mostly accompanied by additional abnormalities. Several known TSGs, namely, the APC, p15/p16, p53, and DCC genes, were found to suffer frequent LOH during lymphomagenesis. LOH was also detected in regions containing putative TSGs on 7q and 13q14. Frequent amplification of genomic material was found in the 2p, 3q27 at the BCL-6 gene locus, 6p, 7q, 11q23-24 at the MLL gene locus, and 18q regions. Analysis of the pattern of occurrence of these aberrations revealed an association of the amplification of the MLL gene region with LOH at the p53 locus (P = .02). Only low frequency of microsatellite instability (MSI) was detected in these lymphomas and MSI incidence increased with age (P = .01). Karyotypic instability thus plays the main role in the development of gastric high-grade large B-cell lymphoma. Common genetic aberrations responsible for lymphomagenesis are deletions of 6q, loss of p53, and amplification of the 3q27 and the MLL gene regions.
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Davenport, Colin F., Tobias Scheithauer, Alessia Dunst, Frauke Sophie Bahr, Marie Dorda, Lutz Wiehlmann y Doan Duy Hai Tran. "Genome-Wide Methylation Mapping Using Nanopore Sequencing Technology Identifies Novel Tumor Suppressor Genes in Hepatocellular Carcinoma". International Journal of Molecular Sciences 22, n.º 8 (11 de abril de 2021): 3937. http://dx.doi.org/10.3390/ijms22083937.
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Downregulation of multiple tumor suppressor genes (TSGs) plays an important role in cancer formation. Recent evidence has accumulated that cancer progression involves genome-wide alteration of epigenetic modifications, which may cause downregulation of the tumor suppressor gene. Using hepatocellular carcinoma (HCC) as a system, we mapped 5-methylcytosine signal at a genome-wide scale using nanopore sequencing technology to identify novel TSGs. Integration of methylation data with gene transcription profile of regenerated liver and primary HCCs allowed us to identify 10 potential tumor suppressor gene candidates. Subsequent validation led us to focus on functionally characterizing one candidate—glucokinase (GCK). We show here that overexpression of GCK inhibits the proliferation of HCC cells via induction of intracellular lactate accumulation and subsequently causes energy crisis due to NAD+ depletion. This suggests GCK functions as a tumor suppressor gene and may be involved in HCC development. In conclusion, these data provide valuable clues for further investigations of the process of tumorigenesis in human cancer.
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Taşpinar, Mehmet. "THE EFFECT OF THE INTERACTIVE SMALL GROUP STUDY METHOD ON DEMOCRATIC ATTITUDES AND SELF-EXPRESSION ABILITY". Social Behavior and Personality: an international journal 34, n.º 9 (1 de enero de 2006): 1115–26. http://dx.doi.org/10.2224/sbp.2006.34.9.1115.
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This study compared the Interactive Small Group Study Method (ISGS) with the Traditional Small Group Study Method (TSGS) from the viewpoint of the student's democratic attitude in the classroom and self-expression ability. Students at Fırat University, Turkey, were divided into an experimental group and a control group each consisting of 30 members. ISGS was applied to the experimental group, TSGS was applied to the control group. The Democratic Attitude Related to Classroom Climate and Self-Expression Ability Scale (AS; Taşpinar, 2001) was given pretest and posttest to both groups. Results showed a significant difference between the pretest and posttest scores of the two groups. The experimental group had a more positive attitude than the control group in the subdivision“Presentation” according to posttest scores. There was no significant difference for the other subdivisions. The ISGS method was found to be more effective than the CSGS method for both democratic attitudes and self-expression ability.
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Wang, Tianfang, Yining Liu y Min Zhao. "Mutational analysis of driver genes with tumor suppressive and oncogenic roles in gastric cancer". PeerJ 5 (17 de julio de 2017): e3585. http://dx.doi.org/10.7717/peerj.3585.
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Gastric cancer (GC) is a complex disease with heterogeneous genetic mechanisms. Genomic mutational profiling of gastric cancer not only expands our knowledge about cancer progression at a fundamental genetic level, but also could provide guidance on new treatment decisions, currently based on tumor histology. The fact that precise medicine-based treatment is successful in a subset of tumors indicates the need for better identification of clinically related molecular tumor phenotypes, especially with regard to those driver mutations on tumor suppressor genes (TSGs) and oncogenes (ONGs). We surveyed 313 TSGs and 160 ONGs associated with 48 protein coding and 19 miRNA genes with both TSG and ONG roles. Using public cancer mutational profiles, we confirmed the dual roles of CDKN1A and CDKN1B. In addition to the widely recognized alterations, we identified another 82 frequently mutated genes in public gastric cancer cohort. In summary, these driver mutation profiles of individual GC will form the basis of personalized treatment of gastric cancer, leading to substantial therapeutic improvements.
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Zhao, Zhujiang, Qingxiang Wu, Jian Cheng, Xuemei Qiu, Jianqiong Zhang y Hong Fan. "Depletion ofDNMT3ASuppressed Cell Proliferation and RestoredPTENin Hepatocellular Carcinoma Cell". Journal of Biomedicine and Biotechnology 2010 (2010): 1–10. http://dx.doi.org/10.1155/2010/737535.
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Promoter hypermethylation mediated by DNA methyltransferases (DNMTs) is the main reason for epigenetic inactivation of tumor suppressor genes (TSGs). Previous studies showed thatDNMT1andDNMT3Bplay an important role in CpG island methylation in tumorigenesis. Little is known about the role ofDNMT3Ain this process, especially in hepatocellular carcinoma (HCC). In the present study, increasedDNMT3Aexpression in 3 out of 6 HCC cell lines and 16/25 (64%) HCC tissues implied thatDNMT3Ais involved in hepatocellular carcinogenesis. Depletion ofDNMT3Ain HCC cell line SMMC-7721 inhibited cell proliferation and decreased the colony formation (about 65%). Microarray data revealed that 153 genes were upregulated in DNMT3A knockdown cells and that almost 71% (109/153) of them contain CpG islands in their5′region. 13 of them includingPTEN, a crucial tumor suppressor gene in HCC, are genes involved in cell cycle and cell proliferation. Demethylation ofPTENpromoter was observed inDNMT3A-depleted cells implying that DNMT3A silencedPTENvia DNA methylation. These results provide insights into the mechanisms ofDNMT3Ato regulate TSGs by an epigenetic approach in HCC.
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Chen, Hui y Zhiying Xu. "Hypermethylation-Associated Silencing of miR-125a and miR-125b: A Potential Marker in Colorectal Cancer". Disease Markers 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/345080.
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Background. MicroRNAs (miRNAs) have been found to be downregulated in human colorectal cancer (CRC), and some of them may function as tumor suppressor genes (TSGs). Aberrant methylation triggers the inactivation of TSGs during tumorigenesis.Patients and Methods. We investigated the methylation status of miR-125 family in CRC tissues and adjacent nontumor tissues by using bisulfite sequencing PCR (BSP). The expression levels of the two miRNAs were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR).Results. The methylation frequency of miR-125a and miR-125b was higher in CRC tissues. QRT-PCR analysis showed that miR-125a and miR-125b were significantly downregulated in CRC tissues. Moreover, the expression levels of miR-125a and miR-125b were inversely correlated to CpG island methylation in CRC.Conclusions. Our results suggest that DNA hypermethylation may be involved in the inactivation of miR-125a and miR-125b in CRC, and hypermethylation of miR-125 is a potential biomarker for clinical outcome.
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Zhang, Y., S. X. Zhang, J. Qiao, R. Zhao, S. Song, Y. Li, M. J. Chang, G. Y. Liu, P. F. He y X. Li. "POS0199 TIME-SERIES ANALYSIS IN MODERATE TO SEVERE PLAQUE PSORIASIS UNDER DIFFERENT BIOLOGICS TREATMENTS". Annals of the Rheumatic Diseases 80, Suppl 1 (19 de mayo de 2021): 315–16. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2669.
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Background:Moderate to Severe Plaque Psoriasis is an inflammatory skin disease that is associated with multiple comorbidities and substantially diminishes patients’ quality of life. As one of the most significant therapeutic advancements in the field of dermatology, Biologics such as TNF inhibitors, IL-12/23 inhibitor, IL-17 inhibitors, and IL-23 inhibitors, have higher efficacy compared with oral medications or phototherapy1. However, the previous studies did not focus on the simultaneous comparison of molecular changes in different classes of biologics. The identification of time-series genes (TSGs) could help to uncover the mechanisms underlying transcriptional regulation2.Objectives:In this study, we aimed to compare the differences in expression patterns and functions of time-series genes in Moderate to Severe Plaque Psoriasis under different biologics treatments.Methods:The transcription profile of GSE117239 and GSE51440 were obtained from the Gene Expression Omnibus database (GEO). The GSE117239 included 19 samples treated with Etanercept (TNF inhibitors) and 16 samples treated with Ustekinumab (IL-12/23 inhibitor). The GSE51440 included 4 samples treated with Guselkumab (IL-23 inhibitors). Skin biopsy samples (LS: lesion, NL: non-lesion) were collected at baseline, weeks 1 and 12, respectively. After background adjustment and other pre-procession, differentially expressed genes (DEGs) were extracted from LS skin biopsy and untreated NL skin biopsy at different times after three different biologics treatments, respectively. The Short Time-series Expression Miner (STEM) software was used to cluster and compare average DEGs with coherent changes. Afterward, the different expression patterns of TSGs under the three treatment groups were compared. GO analysis and KEGG pathway enrichment analysis of TSGs were performed by Metascape.Results:Different DEGs varied in LS skin compared with those of NL skin biopsy: 976 genes in Ustekinumab group, 996 genes in Etanercept group, and 601 genes in Guselkumab group detailly (P < 0.05 and [log FC] > 1). Gene landscapes suggested the signatures of LS gradually changed during the treatment process, and gradually converge to NL signatures (Fig.1a, 2a,3a). Time-series genes in the three treatment groups had different expression patterns and functions. In the Ustekinumab group, a total of 448 TSGs in profile 3 showed a stable-stable-decreasing expression trend and significantly associated with mitotic nuclear division and defense response to other organism, whereas in profile 4 represented a stable-stable-increasing expression trend and significantly associated with positive regulation of cellular response to organic 9 compound (Fig.1). With the treatment of Etanercept, 22 TSGs had a stable-increasing-increasing expression tendency and closely associated with fatty acid metabolism and steroid metabolic process (Fig.2). After Guselkumab treatment, 13 TSGs also represented a stable-increasing-increasing expression tendency that mainly characterized by defense response to other organism and epidermis development (Fig.3). Interestingly, both Ustekinumab and Guselkumab treatment dramatically influenced defense response to other organism-related genes, while Etanercept mainly affected genes involved in fatty acid metabolism and steroid metabolic process.Conclusion:Biologics effectively reconstituted the gene signatures of psoriasis in different aspects. TSG features could be one of indicator for precise intervention for psoriasis.References:[1]Armstrong AW, Read C. Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A Review. Jama 2020;323(19):1945-60. doi: 10.1001/jama.2020.4006 [published Online First: 2020/05/20][2]Ernst J, Bar-Joseph Z. STEM: a tool for the analysis of short time series gene expression data. BMC Bioinformatics 2006;7:191. doi: 10.1186/1471-2105-7-191 [published Online First: 2006/04/07]Acknowledgements:This project was supported by National Science Foundation of China (82001740), Open Fund from the Key Laboratory of Cellular Physiology (Shanxi Medical University) (KLCP2019) and Innovation Plan for Postgraduate Education in Shanxi Province (2020BY078).Disclosure of Interests:None declared
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Vail, Daniel J., Valeria Visconte, Babal K. Jha, Jill Durkin, Jaroslaw Maciejewski y Thomas Laframboise. "Identification of Tumor Suppressors and Synthetic Lethal Targets in -7/del7q Myeloid Neoplasms By Iterative Computational Analysis Coupled with Experimental Validation". Blood 144, Supplement 1 (5 de noviembre de 2024): 4303. https://doi.org/10.1182/blood-2024-210881.
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Complete or partial deletion of chromosome 7 (-7/del7q) is one of the most frequent classes of chromosomal abnormalities found in myeloid malignancies. -7/del7q is distinguished by its poor prognosis, high prevalence among pediatric cases, association with bone marrow failure syndromes, and widespread occurrence among various pathomorphological subtypes of myeloid malignancy (Mori et al.). Despite decades of study, however, the genes responsible for the leukemogenic properties of these deletions are incompletely identified and no targeted therapies matched to the lesion exist (Inaba et al.). Hypothetical candidate mechanisms of -7/del7q pathogenesis include haploinsufficiency and biallelic inactivation of tumor-suppressor genes (TSGs). Deletion may also create clonal vulnerabilities due to haploid loss of genes contained in deleted regions that render clonal cells vulnerable to synthetic-lethal gene (SLG) targeting treatment strategies while leaving normal cells unaffected. To date, these aspects of -7/del(7q) pathogenesis have been tested only on a piecemeal basis, with most studies focusing on identifying haploinsufficient TSGs. Our group has performed extensive computational analyses to query these with the intention of creating a comprehensive understanding of -7/del7q pathogenesis. We have further verified these analyses with selected knockout models (Vail et al, Durkin et al), initiated a wide scale screening effort to comprehensively assay all published -7/del7q potential leukomegenic drivers, and continue to iterate our computational analyses to evolve a detailed map of pathogenic pathways in this context. To these aims, we queried an extensive in-house databank of myeloid neoplasia patients, as well as external data sources. Within this combined cohort are RNA-seq datasets from 29 - 7/del7q patients and WXS/WGS datasets from 47 - 7/del7q patients. We conceptualized TSGs as either haploinsufficient genes or as genes that are biallelically inactivated, where one allele is lost through the deletion event and the other through germline or somatic mutation. To identify this overlooked class of TSGs, we created a biallelic inactivation test, wherein we queried chromosome 7 genes for preferential loss of either the wild-type or a previously mutated allele. We identified 84 genes with a significant preference for loss of the wild-type allele, suggesting these genes are TSGs physiologically inactivated by the second loss-of-function genetic lesion. Among these hits were four genes that are known tumor suppressors in other contexts: TRIM24, CCDC138, SFRP4, and PTPN12. Leukemogenesis in the -7/del7 context may also be driven through the loss of specific combinations of genes. To explore combinatory inactivation of more than one chromosome 7 TSG as a potential leukemogenic mechanism, we expanded the biallelic inactivation test to check for co-mutation amongst chromosome 7 gene pairs. From this, we identified a set of 21 chromosome 7 genes with 33 co-mutation preferences amongst the set, including RAPGEF5: MIOS, TAF6:MCM7, and PMS2:AIMP2. We also sought to identify non-TSG therapeutic targets in -7/del7q lesions. We analyzed expression and mutation signatures to detect compensatory genes that may represent vulnerabilities within cancer cells. We identified hemizygous mutations in our patient data and compared expression levels to diploid patients. As expected, most genes lost in a -7/del7q lesion were commensurately downregulated, but some showed no loss (or even gain) of expression. These upregulated genes may be required for cell survival in cancer cells, but not healthy cells, representing druggable SLG targets. Genes with expression unaffected (or upregulated) by deletion include those whose protein is targetable by an existing small molecule (ABCB5, ADCY1, CYP3A5, EPHA1, NOS3, NPC1L1, SMO), an existing biotherapeutic (monoclonal antibody/enzyme or other protein) (ABCB4, IL6, LAMB1), or both (ABCB1, EGFR, GPER1, MET). This analysis, combined with others focused on identifying haploinsufficient TSGs, comprise a comprehensive and rational atlas of -7/del7q leukemogenic drivers and therapeutic targets. These targets are currently being experimentally confirmed and characterized with the goal of developing targeted small molecule therapies via our in-house drug developmental pipeline to address the unmet clinical need these lesions present.