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Journal articles on the topic 'Gene oncosuppresseur'
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1
Vizioli, M. G., M. Sensi, C. Miranda, L. Cleris, F. Formelli, M. C. Anania, M. A. Pierotti, and A. Greco. "IGFBP7: an oncosuppressor gene in thyroid carcinogenesis." Oncogene 29, no. 26 (May 3, 2010): 3835–44. http://dx.doi.org/10.1038/onc.2010.136.
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Zucchini, C., M. Concu, F. Martini, C. Morelli, N. Salfi, P. Carinci, M. Tognon, and E. Caramelli. "FHIT Oncosuppressor Gene Expression Profile in Human Anal Cancers." International Journal of Biological Markers 22, no. 1 (January 2007): 39–42. http://dx.doi.org/10.1177/172460080702200106.
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The FHIT gene, a member of the histidine triad gene family, is a tumor suppressor gene exhibiting deletions in the majority of human cancers. Aberrant transcripts of this gene have been found in about 50% of esophageal, stomach and colon carcinomas. Little is known about the molecular mechanisms involved in malignant transformation of the lining cells of the anus. In this study FHIT gene expression was investigated in this particular kind of human cancer. FHIT expression was comparatively analyzed at the mRNA level, by RT-PCR, in squamous anal cancers, normal anal tissue and peripheral blood samples. cDNA analyses showed variability in FHIT transcripts, without apparent effects on the predicted amino acid sequence. These different FHIT mRNAs could represent transcripts from an alternative splicing event. Our data indicate that the FHIT mRNA detected in anal cancers and in normal samples is heterogeneous. Immunohistochemical data suggest that the Fhit protein is expressed only in a fraction of the tumor cells, while it is strongly expressed in the epithelial cells of glands of the normal anal mucosa. The absence or poor expression of the Fhit protein in anal cancers suggests a role for this tumor suppressor gene product, as a risk factor, in the onset of this human cancer, as reported before for other human gastrointestinal tumors.
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Zucchini, C., M. Concu, F. Martini, C. Morelli, N. Salfi, P. Carinci, M. Tognon, and E. Caramelli. "FHIT oncosuppressor gene expression profile in human anal cancers." International Journal of Biological Markers 22, no. 1 (2007): 39–42. http://dx.doi.org/10.5301/jbm.2008.3425.
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Lecomte, Fabienne, Bénédicte Champagne, Jean-François Dasnoy, Josiane Szpirer, and Claude Szpirer. "The mammalianRPS6 gene, homolog of theDrosophila air8 tumor suppressor gene: Is it an oncosuppressor gene?" Somatic Cell and Molecular Genetics 21, no. 6 (November 1995): 443–50. http://dx.doi.org/10.1007/bf02310210.
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Thivakaran, Aniththa, Lacramioara Botezatu, Judith Maria Hoenes, Yahya Saleh Al-Matary, Nadine Olberding, Judith Schütte, Renata Köster, Bertram Opalka, Ulrich Dührsen, and Cyrus Khandanpour. "GFI1b As a Novel Oncosuppressor in AML." Blood 128, no. 22 (December 2, 2016): 2717. http://dx.doi.org/10.1182/blood.v128.22.2717.2717.
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Abstract The proper differentiation of hematopoietic stem cells (HSCs) is regulated by a concert of different so called transcription factors (TFs). A disturbed function of these TFs can be the basis of malignant diseases such as acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Growth Factor Independence 1b (Gfi1b) is a repressing transcription factor, with a key role in maintaining the quiescence of HSCs and the proper emergence and maturation of erythrocytes and platelets. Here we show that low expression of GFI1B in blast cells is associated with an inferior prognosis of AML and MDS patients. Using three different mice models of human AML (Nup98-HoxD13, MLL-AF9 and expression of a mutated K-Ras), we could show that reduced expression of Gfi1b accelerates AML development in mice and the latency is even more shortened when Gfi1b is conditionally deleted. Using a limiting dilution assay of transplantation of different number of Gfi1b-wildtype and Gfi1b-deficient cells, we could show that loss of Gfi1b significantly enhanced stemness of leukemic cells. Since Gfii1b is involved in epigenetic regulation of gene expression, we analyzed effect of loss of Gfi1b on an epigenetic level by analyzing the whole genome using Chip-Seq. We found that loss of Gfi1b leads to genome wide increased level of H3K9 acetylation of genes and hence expression of these genes involved in leukemia development. On a molecular level, we found that loss of Gfi1b not only increases the levels of reactive oxygen species (ROS), but also induces gene expression changes of key AML-pathways such as the p38/ AKT pathways. These results demonstrate that Gfi1b functions as an oncosuppressor in MDS/AML development. Disclosures Dührsen: Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding. Khandanpour:Max-Eder: Research Funding; Hospital of Essen university: Research Funding.
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de Biase, Dario, Giorgia Acquaviva, Michela Visani, Viviana Sanza, Chiara M. Argento, Antonio De Leo, Thais Maloberti, Annalisa Pession, and Giovanni Tallini. "Molecular Diagnostic of Solid Tumor Using a Next Generation Sequencing Custom-Designed Multi-Gene Panel." Diagnostics 10, no. 4 (April 23, 2020): 250. http://dx.doi.org/10.3390/diagnostics10040250.
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Next generation sequencing (NGS) allows parallel sequencing of multiple genes at a very high depth of coverage. The need to analyze a variety of targets for diagnostic/prognostic/predictive purposes requires multi-gene characterization. Multi-gene panels are becoming standard approaches for the molecular analysis of solid lesions. We report a custom-designed 128 multi-gene panel engineered to cover the relevant targets in 22 oncogene/oncosuppressor genes for the analysis of the solid tumors most frequently subjected to routine genotyping. A total of 1695 solid tumors were analyzed for panel validation. The analytical sensitivity is 5%. Analytical validation: (i) Accuracy: sequencing results obtained using the multi-gene panel are concordant using two different NGS platforms and single-gene approach sequencing (100% of 83 cases); (ii) Precision: consistent results are obtained in the samples analyzed twice with the same platform (100% of 20 cases). Clinical validation: the frequency of mutations identified in different tumor types is consistent with the published literature. This custom-designed multi-gene panel allows to analyze with high sensitivity and throughput 22 oncogenes/oncosuppressor genes involved in diagnostic/prognostic/predictive characterization of central nervous system tumors, non-small-cell lung carcinomas, colorectal carcinomas, thyroid nodules, pancreatic lesions, melanoma, oral squamous carcinomas and gastrointestinal stromal tumors.
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Manara, Maria Cristina, Ghislaine Bernard, Pier-Luigi Lollini, Patrizia Nanni, Monia Zuntini, Lorena Landuzzi, Stefania Benini, et al. "CD99 Acts as an Oncosuppressor in Osteosarcoma." Molecular Biology of the Cell 17, no. 4 (April 2006): 1910–21. http://dx.doi.org/10.1091/mbc.e05-10-0971.
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CD99 was recently reported to be under control of the osteoblast-specific transcription factor Cbfa1 (RUNX2) in osteoblasts, suggesting a role in the phato-physiology of these cells. No extensive information is available on the role(s) of this molecule in malignant phenotype, and osteosarcoma, in particular, has never been studied. We report that in 11 different cell lines and 17 clinical samples CD99 expression is either undetectable or very low. Being expressed in the normal counterpart, we tested the hypothesis that CD99 down-regulation may have a role in osteosarcoma development and progression. CD99-forced expression in two osteosarcoma cell lines significantly reduced resistance to anoikis, inhibited growth in anchorage independence as well as cell migration, and led to abrogation of tumorigenic and metastatic ability. Therefore, the molecule acts as a potent suppressor of malignancy in osteosarcoma. CD99 gene transfection induces caveolin-1 up-regulation and the two molecules were found to colocalize on the cell surface. Treatment with antisense oligonucleotides to caveolin-1 abrogates the effects of CD99 on migration. The findings point to an antioncogenic role for CD99 in osteosarcoma, likely through the regulation of caveolin-1 and inhibition of c-Src kinase activity.
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Manera, S., S. Bonfiglio, A. Malusà, C. Denis, M. Boussaha, V. Russo, F. Roperto, et al. "Comparative Mapping and Genomic Annotation of the Bovine Oncosuppressor Gene WWOX." Cytogenetic and Genome Research 126, no. 1-2 (2009): 186–93. http://dx.doi.org/10.1159/000245919.
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Hui-Ying, Xue, Zhang Da-Hong, Ji Li-Juan, and Lu Xiao-Jie. "Anticancer Opportunity Created by Loss of Tumor Suppressor Genes." Technology in Cancer Research & Treatment 15, no. 6 (July 9, 2016): 729–31. http://dx.doi.org/10.1177/1533034615604798.
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Deletion of oncosuppressors occurs frequently in the cancer genome. A great deal of effort has been made to therapeutically restore the lost function of oncosuppressors, with little clinically translatable success, however. Reassuringly, besides the disappointing restoration endeavors, oncosuppressor loss can be therapeutically exploited in several other ways, such as the “synthetic lethality” strategies and the “therapeutic vulnerability” created by codeletion of neighboring genes. The study by Liu et al showed that codeletion of p53 and a neighboring essential gene POLR2A rendered colon cancer cells highly sensitive to further inhibition of POLR2A both in vitro and in vivo. In recent years, several studies have reported similar phenomenon in a wide range of cancer types. In this focus article, we will introduce several kinds of anticancer opportunities created by the loss of oncosuppressors and discuss their mechanisms. Given the frequency of oncosuppressor loss in cancer, its therapeutic exploitation rather merits further investigation and may open a new window for oncotherapy.
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Corbetta, S., V. Vaira, V. Guarnieri, A. Scillitani, C. Eller-Vainicher, S. Ferrero, L. Vicentini, et al. "Differential expression of microRNAs in human parathyroid carcinomas compared with normal parathyroid tissue." Endocrine-Related Cancer 17, no. 1 (March 2010): 135–46. http://dx.doi.org/10.1677/erc-09-0134.
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Parathyroid carcinoma (PaC) is a rare cause of primary hyperparathyroidism. Though the loss of the oncosuppressor CDC73/HRPT2 gene product, parafibromin, has been involved in the hyperparathyroidism–jaw tumor syndrome and in a consistent set of sporadic PaCs, parathyroid carcinogenesis remains obscure. MicroRNAs are a new class of small, non-coding RNAs implicated in development of cancer, since their deregulation can induce aberrant expression of several target genes. The aim of the present study was to identify differentially expressed microRNAs in parathyroid cancers compared with normal tissues. We performed a TaqMan low-density array profiling of four parathyroid cancers harboring CDC73 inactivating mutations and negative for parafibromin immunostaining. Their microRNA profiling was compared with that of two normal parathyroid biopsies. Out of 362 human microRNAs assayed, 279 (77%) were successfully amplified. Fourteen and three microRNAs were significantly down- and over-expressed in parathyroid cancers respectively. Of these, miR-296 and miR-139 were down-regulated, and miR-503 and miR-222 were over-expressed with a null false discovery rate. Carcinomas could be discriminated from parathyroid adenomas by a computed score based on the expression levels of miR-296, miR-222, and miR-503 as miR-139 was similarly down-regulated in both cancers and adenomas. Finally, miR-296 and miR-222 levels negatively correlated with mRNA levels of the hepatocyte growth factor receptor-regulated tyrosine kinase substrate and p27/kip1 levels respectively. These results suggest the existence of an altered microRNA expression pattern in PaCs together with a potential role of miR-296 as novel oncosuppressor gene in these neoplasia.
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Keay, Susan, Shreeram C. Nallar, Padmaja Gade, Chen-Ou Zhang, and Dhan V. Kalvakolanu. "Oncosuppressor protein p53 and cyclin-dependent kinase inhibitor p21 regulate interstitial cystitis associated gene expression." Cytokine 110 (October 2018): 110–15. http://dx.doi.org/10.1016/j.cyto.2018.04.029.
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Trifanov, V. S., E. N. Kolesnikov, D. Y. Gvaldin, N. A. Petrusenko, D. S. Potemkin, and M. Y. Mescheryakova. "STUDING THE PROGNOSTIC ROLE OF ONCOSUPPRESSOR GENE METHYLATION IN SPORADIC HIGHLY DIFFERENTIATED NEUROENDOCRINE PANCREATIC TUMORS." Современные проблемы науки и образования (Modern Problems of Science and Education), no. 3 2021 (2021): 118. http://dx.doi.org/10.17513/spno.30892.
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Mirgayazova, Regina, Raniya Khadiullina, Vitaly Chasov, Rimma Mingaleeva, Regina Miftakhova, Albert Rizvanov, and Emil Bulatov. "Therapeutic Editing of the TP53 Gene: Is CRISPR/Cas9 an Option?" Genes 11, no. 6 (June 25, 2020): 704. http://dx.doi.org/10.3390/genes11060704.
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The TP53 gene encodes the transcription factor and oncosuppressor p53 protein that regulates a multitude of intracellular metabolic pathways involved in DNA damage repair, cell cycle arrest, apoptosis, and senescence. In many cases, alterations (e.g., mutations of the TP53 gene) negatively affect these pathways resulting in tumor development. Recent advances in genome manipulation technologies, CRISPR/Cas9, in particular, brought us closer to therapeutic gene editing for the treatment of cancer and hereditary diseases. Genome-editing therapies for blood disorders, blindness, and cancer are currently being evaluated in clinical trials. Eventually CRISPR/Cas9 technology is expected to target TP53 as the most mutated gene in all types of cancers. A majority of TP53 mutations are missense which brings immense opportunities for the CRISPR/Cas9 system that has been successfully used for correcting single nucleotides in various models, both in vitro and in vivo. In this review, we highlight the recent clinical applications of CRISPR/Cas9 technology for therapeutic genome editing and discuss its perspectives for editing TP53 and regulating transcription of p53 pathway genes.
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Kuo, Yuan-Sung, Yueh-Bih Tang, Tung-Ying Lu, Han-Chung Wu, and Chin-Tarng Lin. "IGFBP-6 plays a role as an oncosuppressor gene in NPC pathogenesis through regulating EGR-1 expression." Journal of Pathology 222, no. 3 (May 21, 2010): 299–309. http://dx.doi.org/10.1002/path.2735.
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García-Sancha, Natalia, Roberto Corchado-Cobos, Jesús Pérez-Losada, and Javier Cañueto. "MicroRNA Dysregulation in Cutaneous Squamous Cell Carcinoma." International Journal of Molecular Sciences 20, no. 9 (May 2, 2019): 2181. http://dx.doi.org/10.3390/ijms20092181.
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Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and it can be locally invasive and metastatic to distant sites. MicroRNAs (miRNAs or miRs) are endogenous, small, non-coding RNAs of 19–25 nucleotides in length, that are involved in regulating gene expression at a post-transcriptional level. MicroRNAs have been implicated in diverse biological functions and diseases. In cancer, miRNAs can proceed either as oncogenic miRNAs (onco-miRs) or as tumor suppressor miRNAs (oncosuppressor-miRs), depending on the pathway in which they are involved. Dysregulation of miRNA expression has been shown in most of the tumors evaluated. MiRNA dysregulation is known to be involved in the development of cutaneous squamous cell carcinoma (CSCC). In this review, we focus on the recent evidence about the role of miRNAs in the development of CSCC and in the prognosis of this form of skin cancer.
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Garlanda, Cecilia, Barbara Bottazzi, Elena Magrini, Antonio Inforzato, and Alberto Mantovani. "PTX3, a Humoral Pattern Recognition Molecule, in Innate Immunity, Tissue Repair, and Cancer." Physiological Reviews 98, no. 2 (April 1, 2018): 623–39. http://dx.doi.org/10.1152/physrev.00016.2017.
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Innate immunity includes a cellular and a humoral arm. PTX3 is a fluid-phase pattern recognition molecule conserved in evolution which acts as a key component of humoral innate immunity in infections of fungal, bacterial, and viral origin. PTX3 binds conserved microbial structures and self-components under conditions of inflammation and activates effector functions (complement, phagocytosis). Moreover, it has a complex regulatory role in inflammation, such as ischemia/reperfusion injury and cancer-related inflammation, as well as in extracellular matrix organization and remodeling, with profound implications in physiology and pathology. Finally, PTX3 acts as an extrinsic oncosuppressor gene by taming tumor-promoting inflammation in murine and selected human tumors. Thus evidence suggests that PTX3 is a key homeostatic component at the crossroad of innate immunity, inflammation, tissue repair, and cancer. Dissecting the complexity of PTX3 pathophysiology and human genetics paves the way to diagnostic and therapeutic exploitation.
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Sellitto, Assunta, Ylenia D’Agostino, Elena Alexandrova, Jessica Lamberti, Giovanni Pecoraro, Domenico Memoli, Domenico Rocco, et al. "Insights into the Role of Estrogen Receptor β in Triple-Negative Breast Cancer." Cancers 12, no. 6 (June 5, 2020): 1477. http://dx.doi.org/10.3390/cancers12061477.
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Estrogen receptors (ERα and ERβ) are ligand-activated transcription factors that play different roles in gene regulation and show both overlapping and specific tissue distribution patterns. ERβ, contrary to the oncogenic ERα, has been shown to act as an oncosuppressor in several instances. However, while the tumor-promoting actions of ERα are well-known, the exact role of ERβ in carcinogenesis and tumor progression is not yet fully understood. Indeed, to date, highly variable and even opposite effects have been ascribed to ERβ in cancer, including for example both proliferative and growth-inhibitory actions. Recently ERβ has been proposed as a potential target for cancer therapy, since it is expressed in a variety of breast cancers (BCs), including triple-negative ones (TNBCs). Because of the dependence of TNBCs on active cellular signaling, numerous studies have attempted to unravel the mechanism(s) behind ERβ-regulated gene expression programs but the scenario has not been fully revealed. We comprehensively reviewed the current state of knowledge concerning ERβ role in TNBC biology, focusing on the different signaling pathways and cellular processes regulated by this transcription factor, as they could be useful in identifying new diagnostic and therapeutic approaches for TNBC.
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Gorbacheva, A. M., A. K. Eremkina, and N. G. Mokrysheva. "Bone disorders in type 1 multiple endocrine neoplasia syndrome: A review of clinical data." Rheumatology Science and Practice 59, no. 1 (March 3, 2021): 97–102. http://dx.doi.org/10.47360/1995-4484-2021-97-102.
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Primary hyperparathyroidism (PHPT) is a result of the parathyroid tumors, usually manifesting by elevated serum parathyroid hormone and hypercalcemia. One of the most common complications of PHPT are bone disorders. It mainly occurs as sporadic disease, while the remaining 5–10% is the component of hereditary syndromes, more often – type 1 multiple endocrine neoplasia syndrome (MEN1). MEN1 is caused by the germinal mutation of the oncosuppressor menin gene, founded in all cells of the human body, including the osteogenic cells. Data on the bone state in MEN1 is limited and contradictory. At the same time, some studies indicate that MEN1-related PHPT differs from sporadic form in bone manifestation, which can be presumably associated with the inadequate functioning of mutant menin. The results of experimental works suggest that menin plays an important role in the metabolism and differentiation of bone cells. This article is a literature review on this problem and contains information on the current clinical data on the bone state in patients with MEN1.
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Sasatomi, Eizaburo, Osamu Tokunaga, and Kohji Miyazaki. "Spontaneous apoptosis in gallbladder carcinoma: Relationships with clinicopathologic factors, expression of E-cadherin,bcl-2 protooncogene, and p53 oncosuppressor gene." Cancer 78, no. 10 (November 15, 1996): 2101–10. http://dx.doi.org/10.1002/(sici)1097-0142(19961115)78:10<2101::aid-cncr10>3.0.co;2-2.
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Porrello, Alessandro, Maria Antonietta Cerone, Sabrina Coen, Aymone Gurtner, Giulia Fontemaggi, Letizia Cimino, Giulia Piaggio, Ada Sacchi, and Silvia Soddu. "P53 Regulates Myogenesis by Triggering the Differentiation Activity of Prb." Journal of Cell Biology 151, no. 6 (December 11, 2000): 1295–304. http://dx.doi.org/10.1083/jcb.151.6.1295.
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The p53 oncosuppressor protein regulates cell cycle checkpoints and apoptosis, but increasing evidence also indicates its involvement in differentiation and development. We had previously demonstrated that in the presence of differentiation-promoting stimuli, p53-defective myoblasts exit from the cell cycle but do not differentiate into myocytes and myotubes. To identify the pathways through which p53 contributes to skeletal muscle differentiation, we have analyzed the expression of a series of genes regulated during myogenesis in parental and dominant–negative p53 (dnp53)-expressing C2C12 myoblasts. We found that in dnp53-expressing C2C12 cells, as well as in p53−/− primary myoblasts, pRb is hypophosphorylated and proliferation stops. However, these cells do not upregulate pRb and have reduced MyoD activity. The transduction of exogenous TP53 or Rb genes in p53-defective myoblasts rescues MyoD activity and differentiation potential. Additionally, in vivo studies on the Rb promoter demonstrate that p53 regulates the Rb gene expression at transcriptional level through a p53-binding site. Therefore, here we show that p53 regulates myoblast differentiation by means of pRb without affecting its cell cycle–related functions.
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Ganakammal, Satishkumar Ranganathan, Mahesh Koirala, Bohua Wu, and Emil Alexov. "In-silico analysis to identify the role of MEN1 missense mutations in breast cancer." Journal of Theoretical and Computational Chemistry 19, no. 06 (June 30, 2020): 2041002. http://dx.doi.org/10.1142/s0219633620410023.
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Background: The multiple endocrine neoplasia type 1 (MEN1) gene located on chromosome 11q13 encodes menin protein. Previously reported mutations were thought to result in loss of function of menin protein and that they are associated with multiple endocrine neoplasia 1 disorder. However, recently menin has also been characterized as an oncosuppressor protein and it was suggested that mutations in it are associated with various other tumors. Studies indicate that the menin protein stimulates the estrogen receptor (ER) that in turn increases the predisposition for inherited breast cancer. Methods: Here, we used our supervised in-house combinatory in-silico predictor method to investigate the impact of unclassified missense mutations in MEN1 gene found in breast cancer tissue. We also examined the biophysical and biochemical properties to predict the effects of these missense variants on the menin protein stability and interactions. The results are compared with the effects of known pathogenic mutations in menin causing neoplasia. Results: Our analysis indicates that some of the variants found in breast cancer tissue show similar pattern of destabilizing the menin protein and its interactions as the pathogenic variants associated with neoplasia. Taking together with the results of our in-silico consensus predictor, we classify missense mutations in menin protein found in breast cancer tissue into pathogenic and benign, and thus, suggesting as an indicator for early detection of elevated breast cancer risk.
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Ashrafizadeh, Milad, Zahra Ahmadi, Tahereh Farkhondeh, and Saeed Samarghandian. "Anti-tumor Activity of Propofol: A Focus on MicroRNAs." Current Cancer Drug Targets 20, no. 2 (February 11, 2020): 104–14. http://dx.doi.org/10.2174/1568009619666191023100046.
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Background:: MicroRNAs are endogenous, short, non-coding RNAs with the length as low as 20 to 25 nucleotides. These RNAs are able to negatively affect the gene expression at the post-transcriptional level. It has been demonstrated that microRNAs play a significant role in cell proliferation, cell migration, cell death, cell differentiation, infection, immune response, and metabolism. Besides, the dysfunction of microRNAs has been observed in a variety of cancers. So, modulation of microRNAs is of interest in the treatment of disorders. Objective:: The aim of the current review is to investigate the modulatory effect of propofol on microRNAs in cancer therapy. Methods: : This review was performed at PubMed, SCOPUS and Web of Science data-bases using keywords “propofol’, “microRNA”, “cancer therapy”, “propofol + microRNA” and “propofol + miR”. Results:: It was found that propofol dually down-regulates/upregulates microRNAs to exert its antitumor activity. In terms of oncogenesis microRNAs, propofol exert an inhibitory effect, while propofol significantly enhances the expression of oncosuppressor microRNAs. Conclusion:: It seems that propofol is a potential modulator of microRNAs and this capability can be used in the treatment of various cancers.
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Nagachinta, Surasa, Belen Lopez Bouzo, Abi Judit Vazquez-Rios, Rafael Lopez, and Maria de la Fuente. "Sphingomyelin-Based Nanosystems (SNs) for the Development of Anticancer miRNA Therapeutics." Pharmaceutics 12, no. 2 (February 22, 2020): 189. http://dx.doi.org/10.3390/pharmaceutics12020189.
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Gene replacement therapy with oncosuppressor microRNAs (miRNAs) is a promising alternative to interfere with cancer progression. However, miRNAs are highly inefficient in a biological environment, hampering a successful translation to clinics. Nanotechnology can tackle this drawback by providing delivery systems able to efficiently deliver them to cancer cells. Thus, the objective of this work was to develop biocompatible nanosystems based on sphingomyelin (SM) for the intracellular delivery of miRNAs to colorectal cancer cells. We pursued two different approaches to select the most appropriate composition for miRNA delivery. On the one hand, we prepared sphingomyelin-based nanosystems (SNs) that incorporate the cationic lipid stearylamine (ST) to support the association of miRNA by the establishment of electrostatic interactions (SNs–ST). On the other hand, the cationic surfactant (DOTAP) was used to preform lipidic complexes with miRNA (Lpx), which were further encapsulated into SNs (SNs-Lpx). Restitution of miRNA145 levels after transfection with SNs-Lpx was related to the strongest anticancer effect in terms of tumor proliferation, colony forming, and migration capacity assays. Altogether, our results suggest that SNs have the potential for miRNA delivery to develop innovative anticancer therapies.
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Ali Syeda, Zainab, Siu Semar Saratu’ Langden, Choijamts Munkhzul, Mihye Lee, and Su Jung Song. "Regulatory Mechanism of MicroRNA Expression in Cancer." International Journal of Molecular Sciences 21, no. 5 (March 3, 2020): 1723. http://dx.doi.org/10.3390/ijms21051723.
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Altered gene expression is the primary molecular mechanism responsible for the pathological processes of human diseases, including cancer. MicroRNAs (miRNAs) are virtually involved at the post-transcriptional level and bind to 3′ UTR of their target messenger RNA (mRNA) to suppress expression. Dysfunction of miRNAs disturbs expression of oncogenic or tumor-suppressive target genes, which is implicated in cancer pathogenesis. As such, a large number of miRNAs have been found to be downregulated or upregulated in human cancers and to function as oncomiRs or oncosuppressor miRs. Notably, the molecular mechanism underlying the dysregulation of miRNA expression in cancer has been recently uncovered. The genetic deletion or amplification and epigenetic methylation of miRNA genomic loci and the transcription factor-mediated regulation of primary miRNA often alter the landscape of miRNA expression in cancer. Dysregulation of the multiple processing steps in mature miRNA biogenesis can also cause alterations in miRNA expression in cancer. Detailed knowledge of the regulatory mechanism of miRNAs in cancer is essential for understanding its physiological role and the implications of cancer-associated dysfunction and dysregulation. In this review, we elucidate how miRNA expression is deregulated in cancer, paying particular attention to the cancer-associated transcriptional and post-transcriptional factors that execute miRNA programs.
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Tritarelli, A., E. Oricchio, M. Ciciarello, R. Mangiacasale, A. Palena, P. Lavia, S. Soddu, and E. Cundari. "p53 Localization at Centrosomes during Mitosis and Postmitotic Checkpoint Are ATM-dependent and Require Serine 15 Phosphorylation." Molecular Biology of the Cell 15, no. 8 (August 2004): 3751–57. http://dx.doi.org/10.1091/mbc.e03-12-0900.
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We recently demonstrated that the p53 oncosuppressor associates to centrosomes in mitosis and this association is disrupted by treatments with microtubule-depolymerizing agents. Here, we show that ATM, an upstream activator of p53 after DNA damage, is essential for p53 centrosomal localization and is required for the activation of the postmitotic checkpoint after spindle disruption. In mitosis, p53 failed to associate with centrosomes in two ATM-deficient, ataxiatelangiectasia–derived cell lines. Wild-type ATM gene transfer reestablished the centrosomal localization of p53 in these cells. Furthermore, wild-type p53 protein, but not the p53-S15A mutant, not phosphorylatable by ATM, localized at centrosomes when expressed in p53-null K562 cells. Finally, Ser15 phosphorylation of endogenous p53 was detected at centrosomes upon treatment with phosphatase inhibitors, suggesting that a p53 dephosphorylation step at centrosome contributes to sustain the cell cycle program in cells with normal mitotic spindles. When dissociated from centrosomes by treatments with spindle inhibitors, p53 remained phosphorylated at Ser15. AT cells, which are unable to phosphorylate p53, did not undergo postmitotic proliferation arrest after nocodazole block and release. These data demonstrate that ATM is required for p53 localization at centrosome and support the existence of a surveillance mechanism for inhibiting DNA reduplication downstream of the spindle assembly checkpoint
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Pascale, Peitta, Simile, and Feo. "Alterations of Methionine Metabolism as Potential Targets for the Prevention and Therapy of Hepatocellular Carcinoma." Medicina 55, no. 6 (June 21, 2019): 296. http://dx.doi.org/10.3390/medicina55060296.
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Several researchers have analyzed the alterations of the methionine cycle associated with liver disease to clarify the pathogenesis of human hepatocellular carcinoma (HCC) and improve the preventive and the therapeutic approaches to this tumor. Different alterations of the methionine cycle leading to a decrease of S-adenosylmethionine (SAM) occur in hepatitis, liver steatosis, liver cirrhosis, and HCC. The reproduction of these changes in MAT1A-KO mice, prone to develop hepatitis and HCC, demonstrates the pathogenetic role of MAT1A gene under-regulation associated with up-regulation of the MAT2A gene (MAT1A:MAT2A switch), encoding the SAM synthesizing enzymes, methyladenosyltransferase I/III (MATI/III) and methyladenosyltransferase II (MATII), respectively. This leads to a rise of MATII, inhibited by the reaction product, with a consequent decrease of SAM synthesis. Attempts to increase the SAM pool by injecting exogenous SAM have beneficial effects in experimental alcoholic and non-alcoholic steatohepatitis and hepatocarcinogenesis. Mechanisms involved in hepatocarcinogenesis inhibition by SAM include: (1) antioxidative effects due to inhibition of nitric oxide (NO•) production, a rise in reduced glutathione (GSH) synthesis, stabilization of the DNA repair protein Apurinic/Apyrimidinic Endonuclease 1 (APEX1); (2) inhibition of c-myc, H-ras, and K-ras expression, prevention of NF-kB activation, and induction of overexpression of the oncosuppressor PP2A gene; (3) an increase in expression of the ERK inhibitor DUSP1; (4) inhibition of PI3K/AKT expression and down-regulation of C/EBPα and UCA1 gene transcripts; (5) blocking LKB1/AMPK activation; (6) DNA and protein methylation. Different clinical trials have documented curative effects of SAM in alcoholic liver disease. Furthermore, SAM enhances the IFN-α antiviral activity and protects against hepatic ischemia-reperfusion injury during hepatectomy in HCC patients with chronic hepatitis B virus (HBV) infection. However, although SAM prevents experimental tumors, it is not curative against already established experimental and human HCCs. The recent observation that the inhibition of MAT2A and MAT2B expression by miRNAs leads to a rise of endogenous SAM and strong inhibition of cancer cell growth could open new perspectives to the treatment of HCC.
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Ceresoli, G. L., A. Destro, E. Baryshnikova, I. Garassino, P. A. Zucali, E. Morenghi, A. Testori, M. Alloisio, M. Roncalli, and A. Santoro. "DNA methylation profile predicts survival of patients with resected malignant pleural mesothelioma (MPM)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 7712. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.7712.
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7712 Background: Methylation in different tumor suppressor genes is among the most frequent alterations reported in MPM patients (pts). DNA methylation increases upon immortalization and transformation of human mesothelial cells, and demethylating agents were found to have some activity in MPM. In this study we analysed the methylation status of the promoter region of four candidate genes in MPM: p15INK4BINK4B, p16INK4AINK4A, RASSF1A and NORE1A. Methods: Samples of 79 consecutive MPM pts who underwent surgical procedures (41 extrapleural pneumonectomy (EPP), 32 partial pleurectomy, 6 diagnostic biopsy) at our Institution from 1997 to 2005 were analyzed. DNA was isolated from each paraffin-embedded MPM; the methylation status of the four genes was evaluated by a methylation-specific PCR method (MSP). Correlations between methylation status, clinico-pathological parameters (including proliferation index) and overall survival (OS) were examined in all pts and in the EPP subgroup. Proliferation index was evaluated as percentage of nuclear immunoreactivity/10 high-power field using a mouse monoclonal antibody anti-human Ki-67, clone MIB-1 (DAKO Corporation, Carpinteria, CA). Results: The MSP analysis documented gene promoter methylation in at least one gene in 30 cases (38%). The methylation frequency of each gene was: p15INK4B 15 cases (19%), p16INK4A 9 (11.4%), RASSF1A 16 (20.2%), Nore1A 4 (5.1%). Of the 30 methylated MPMs, 18 (60%) showed only one methylated gene, 10 (33.3%) were methylated in two genes and 2 (6.7%) in three. Methylation in at least one gene was associated to a higher proliferation index (P=0.058, ANOVA), but not to OS, in the whole study population. In pts treated with EPP, the 22 methylated cases showed a trend to a worst OS in comparison to 19 unmethylated cases (median OS 16 months vs 35 months, P=0.066, HR=2.01, 95% CI 0.94–4.30, Cox regression), independently by histology and nodal status. Conclusions: In pts treated with EPP, the methylation profile of p15INK4BINK4B, p16INK4AINK4A, RASSF1A and NORE1A appeared to be an independent prognostic factor for OS. The methylation status was correlated to proliferation rate, indicating a potential role of these oncosuppressor genes in the neoplastic progression of MPM. No significant financial relationships to disclose.
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Casalino, Laura, and Pasquale Verde. "Multifaceted Roles of DNA Methylation in Neoplastic Transformation, from Tumor Suppressors to EMT and Metastasis." Genes 11, no. 8 (August 12, 2020): 922. http://dx.doi.org/10.3390/genes11080922.
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Among the major mechanisms involved in tumorigenesis, DNA methylation is an important epigenetic modification impacting both genomic stability and gene expression. Methylation of promoter-proximal CpG islands (CGIs) and transcriptional silencing of tumor suppressors represent the best characterized epigenetic changes in neoplastic cells. The global cancer-associated effects of DNA hypomethylation influence chromatin architecture and reactivation of repetitive elements. Moreover, recent analyses of cancer cell methylomes highlight the role of the DNA hypomethylation of super-enhancer regions critically controlling the expression of key oncogenic players. We will first summarize some basic aspects of DNA methylation in tumorigenesis, along with the role of dysregulated DNA methyltransferases and TET (Ten-Eleven Translocation)-family methylcytosine dioxygenases. We will then examine the potential contribution of epimutations to causality and heritability of cancer. By reviewing some representative genes subjected to hypermethylation-mediated silencing, we will survey their oncosuppressor functions and roles as biomarkers in various types of cancer. Epithelial-to-mesenchymal transition (EMT) and the gain of stem-like properties are critically involved in cancer cell dissemination, metastasis, and therapeutic resistance. However, the driver vs passenger roles of epigenetic changes, such as DNA methylation in EMT, are still poorly understood. Therefore, we will focus our attention on several aspects of DNA methylation in control of EMT and metastasis suppressors, including both protein-coding and noncoding genes.
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Tavanti, Giulia Stefania, Chiara Verdelli, Annamaria Morotti, Paola Maroni, Vito Guarnieri, Alfredo Scillitani, Rosamaria Silipigni, et al. "Yes-Associated Protein 1 Is a Novel Calcium Sensing Receptor Target in Human Parathyroid Tumors." International Journal of Molecular Sciences 22, no. 4 (February 18, 2021): 2016. http://dx.doi.org/10.3390/ijms22042016.
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The Hippo pathway is involved in human tumorigenesis and tissue repair. Here, we investigated the Hippo coactivator Yes-associated protein 1 (YAP1) and the kinase large tumor suppressor 1/2 (LATS1/2) in tumors of the parathyroid glands, which are almost invariably associated with primary hyperparathyroidism. Compared with normal parathyroid glands, parathyroid adenomas (PAds) and carcinomas show variably but reduced nuclear YAP1 expression. The kinase LATS1/2, which phosphorylates YAP1 thus promoting its degradation, was also variably reduced in PAds. Further, YAP1 silencing reduces the expression of the key parathyroid oncosuppressor multiple endocrine neoplasia type 1(MEN1), while MEN1 silencing increases YAP1 expression. Treatment of patient-derived PAds-primary cell cultures and Human embryonic kidney 293A (HEK293A) cells expressing the calcium-sensing receptor (CASR) with the CASR agonist R568 induces YAP1 nuclear accumulation. This effect was prevented by the incubation of the cells with RhoA/Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitors Y27632 and H1152. Lastly, CASR activation increased the expression of the YAP1 gene targets CYR61, CTGF, and WNT5A, and this effect was blunted by YAP1 silencing. Concluding, here we provide preliminary evidence of the involvement of the Hippo pathway in human tumor parathyroid cells and of the existence of a CASR-ROCK-YAP1 axis. We propose a tumor suppressor role for YAP1 and LATS1/2 in parathyroid tumors.
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Spirina, Lyidmila, Svetlana Chizhevskaya, Irina Kondakova, Evgeny Choynzonov, and Irina Kovaleva. "VHL expression in case of thyroid tumor pathology: connection with the prevalence of the disease, expression of transcription, growth factors and components of the AKT / m-TOR signaling pathway." Problems in oncology 67, no. 1 (March 4, 2021): 117–22. http://dx.doi.org/10.37469/0507-3758-2021-67-1-117-122.
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Introduction. The oncosuppressor protein VHL plays a decisive or at least important role in the mechanisms of tumor progression. The development of malignant neoplasms of the thyroid gland is associated with the activation of transcriptional and growth factors. However, the role of the VHL gene in the mechanisms of the development of thyroid cancer has hardly been studied. The study aimed to study the clinical and morphological features, expression of transcription, growth factors, and components of the AKT / m-TOR signaling pathway in patients with papillary thyroid cancer depending on the level of expression of the VHL gene. Material and methods. The study included 46 patients with tumor pathology of the thyroid gland: 20 patients with benign thyroid tumors and 26 patients with papillary thyroid cancer T1-4N0-2M0. The expression of parameters was determined by PCR in real-time. Mutation BRAF-V600E was determined in allele-specific PCR in real-time. Results and their discussion. The mRNA level of the VHL gene remained virtually unchanged in the tissue of papillary cancer and benign thyroid tumors. It depended on the prevalence of the disease, the defeat of regional lymph nodes, and the BRAF-V600E status. In the presence of the BRAF-V600E mutation, VHL expression increased 615 times in patients with a mutation compared with patients without this somatic mutation. It was revealed that the expression of NF-κB p65, NF-κB p50, HIF-1, HIF-2, growth factors VEGF and CAIX in patients in the group with a VHL level> 1.0 RU increased compared with patients with a VHL level <1.0 RU. A decrease in PDK, c-RAF, mTOR, 70s 6 kinase, PTEN mRNA levels were also recorded in patients with increased levels of VHL expression compared with patients with VHL expression <1.0 RU. Conclusion. That the association of the VHL expression with tumor progression in papillary thyroid cancer and the mutant protein bRAF presence was found. Also, associations between the VHL expression and the level of mRNA of transcription and growth factors are noted.
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Mustafin, R. N., M. A. Bermisheva, R. R. Valiev, and E. E. Khusnutdinova. "Neurofibromatosis type 1: results of our own study (Republic of Bashkortostan)." Advances in Molecular Oncology 8, no. 1 (May 9, 2021): 17–25. http://dx.doi.org/10.17650/2313-805x-2021-8-1-17-25.
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Introduction. Neurofibromatosis type 1 (NF1) is the most common hereditary tumor syndrome (frequency of its occurrence in the world is 1 : 3000 of the population). The main clinical manifestations of the disease are multiple café-au-lait macules on the skin and neurofibromas, skeletal abnormalities and cognitive deficits. The disease is based on mutations in the oncosuppressor gene NF1. This disease is characterized by significant clinical polymorphism of manifestations, even among members of the same family. No geno-phenotypic correlations were found for NF1. Therefore, it is assumed that modifier genes are the cause of the varying expressiveness of the disease. Materials and methods. Clinical-epidemiological and molecular-genetic research of patients with NF1 in the Republic of Bashkortostan (RB) was carried out. Sequencing was used to search for intragenic mutations in 57 exons of the NF1 gene. Microsatellite analysis was used to detect the deletion of the entire gene.Results. The frequency of occurrence of NF1 in RB was 1 : 10153 of the population. Analysis of the clinical manifestations of NF1 in RB patients showed a lower incidence of brain cysts in patients born in mixed marriages, which indicates the protective role of mestization. In patients with NF1 who inherited the disease from the mother, a more frequent development of skeletal anomalies and facial dysmorphism was determined. We identified 1 deletion of the entire NF1 gene in 1 patient and 14 intragenic mutations (c.205-1G>C, с.1278G>A, c.1369_1370insGGGTC, с.1570G>A, с.1973_1974delTC, c.2806A>T, с.2991-1G>C, c.3158C>G, с.3526_3528delAGA, с.3826delC, с.4514+5G>A, с.4537С>Т, c.5758_5761delTTGA, с.6792С>A) in 20 patients with NF1. We determined the random distribution of the types of mutations and did not reveal the specific features of the NF1 clinic depending on the type of mutations.Conclusions. The protective role of crossbreeding in relation to brain cysts, as well as the predominance of skeletal anomalies in patients with NF1 inheritance from the mother, indicate the role of modifier genes in the pathogenesis of the disease. The identified mutations in the NF1 gene will allow us to perform prenatal prevention of NF1 in RB patients.
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Laera, Luna, Nicoletta Guaragnella, Sergio Giannattasio, and Loredana Moro. "6-Thioguanine and Its Analogs Promote Apoptosis of Castration-Resistant Prostate Cancer Cells in a BRCA2-Dependent Manner." Cancers 11, no. 7 (July 5, 2019): 945. http://dx.doi.org/10.3390/cancers11070945.
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Background: Mutations in the oncosuppressor gene BReast CAncer susceptibility gene 2 (BRCA2) predispose to aggressive forms of prostate cancer which show poor response to taxane-based therapy, the standard treatment for castration-resistant, aggressive prostate cancer. Herein, we addressed the question whether changes in BRCA2 expression, a potential surrogate marker for BRCA2 activity, may affect the response of castration-resistant prostate cancer cells to 6-thioguanine (6-TG), a thiopurine used in the treatment of haematological malignancies. Methods: Yeast, normal prostate cells and castration-resistant prostate cancer cells were treated with 6-TG or its analogues, in presence or absence of paclitaxel, or with olaparib, a poly-(ADP-ribose) polymerase (PARP) inhibitor currently in clinical trials for treatment of metastatic castration-resistant prostate cancer, and cell proliferation, apoptosis and androgen receptor (AR) levels were measured. Results: 6-TG inhibited cell proliferation in yeast, normal and castration-resistant prostate cancer cells but promoted apoptosis only in cancer cells. Suppression of BRCA2 expression by siRNA or shRNA increased the sensitivity to 6-TG- and olaparib-induced apoptosis but did not affect cancer cell response to taxane. Intriguingly, 6-TG reduced AR expression levels independently on BRCA2 expression. Instead, olaparib decreased AR levels only in BRCA2-knockdown prostate cancer cells. Notably, overexpression of BRCA2 resulted in resistance of castration-resistant prostate cancer cells to 6-TG-, taxane- and olaparib-based treatment but promoted sensitivity to apoptosis induced by 2-amino-6-bromopurine and 2,6–dithiopurine, two 6-TG analogues. Conclusions: Our results provide a pre-clinical rationale for the use of 6-TG in the treatment of BRCA2-deficient castration-resistant prostate cancers, and of certain 6-TG analogues for treatment of BRCA2-proficient prostate cancers.
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Sicouri, Lara, Federica Pisati, Salvatore Pece, Francesco Blasi, and Elena Longobardi. "Prep1 (pKnox1) transcription factor contributes to pubertal mammary gland branching morphogenesis." International Journal of Developmental Biology 62, no. 11-12 (2018): 827–36. http://dx.doi.org/10.1387/ijdb.180278fb.
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Prep1 (pKnox1) is a homeodomain transcription factor essential for in utero and post-natal development and an oncosuppressor gene in human and adult mice. We have analyzed its role in the development of the mouse mammary gland. We used Prep1i/i hypomorphic and Prep1F/F-Ker5CRE crosses to analyze the role of Prep1 in vivo in adult mouse mammary gland development. We also cultured mammary gland stem/progenitor cells in mammospheres to perform biochemical studies. Prep1 was expressed in mammary gland progenitors and fully differentiated mammary gland cells. Using different Prep1-deficient mouse models we show that in vivo Prep1 contributes to mammary gland branching since the branching efficiency of the mammary gland in Prep1-deleted or Prep1 hypomorphic mice was largely reduced. In-vitro, Prep1 sustained functions of the mammary stem/progenitor compartment. Prep1-deficient mammary stem/progenitor cells showed reduced ability to form mammospheres; they were not able to branch in a 3D assay, and exhibited reduced expression of Snail1, Snail2 and vimentin. The branching phenotype associated with increased Tp53-dependent apoptosis and inability to properly activate signals involved in branching morphogenesis. Finally, Prep1 formed complexes with Snail2, a transcription factor essential in branching morphogenesis, and its absence destabilizes and promotes Snail2 proteasome-mediated degradation. We conclude that Prep1 is required for normal adult mammary gland development, in particular at its branching morphogenesis step. By binding Snail2, Prep1 protects it from the proteasomal degradation.
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Giaretti, Walter, Barbara Macciocu, Elio Geido, Mario Hermsen, Cindy Postma, Jan Baak, Richard Williams, and Gerrit Meijer. "Intratumor Heterogeneity of K-Ras and p53 Mutations among Human Colorectal Adenomas Containing Early Cancer." Analytical Cellular Pathology 21, no. 2 (2000): 49–57. http://dx.doi.org/10.1155/2000/747524.
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The molecular pathways and the timing of genetic events during human colorectal carcinogenesis are still not fully understood. We have addressed the intratumor heterogeneity of the mutational status of the k‐ras oncogene and of the p53 oncosuppressor gene during the adenoma–carcinoma sequence by investigating 26 human colorectal adenomas containing early cancer. An intratumor comparative analysis was obtained among the adenomatous and carcinomatous component pairs. Additionally, we have analyzed 17 adenomas having cancer in the near vicinity. The adenomatous components of the adenomas containing early cancer and the adenomas having cancer in the near vicinity had comparable frequencies for k‐ras mutations (28 and 47%) but different for p53 mutations (52 and 7%,p‐value = 0.01). Interestingly, the adenomatous and carcinomatous components of the adenomas containing early cancer were rarely heterogeneous for the k‐ras mutational status (only in 13% of the cases) but were characterized by heterogeneity of the p53 status in 59% of the cases (p‐value < 0.01). In addition, the mutations of p53 for the adenomatous components of the adenomas containing early cancer were statistically significantly associated with severe dysplasia (p-value = 0.01). Intratumor homogeneity of k‐ras status during the human colorectal adenoma–carcinoma sequence suggests that the role of k‐ras is more related to tumor initiation than to tumor progression. On the contrary, intratumor heterogeneity of p53 mutations indicates that the type of the p53 mutations may also be relevant for selection and expansion of new subclones leading to tumor progression.
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Porta, Giuseppe Della, Paolo Radice, and Marco A. Pierotti. "Onco-Suppressor Genes in Human Cancer." Tumori Journal 75, no. 4 (August 1989): 329–36. http://dx.doi.org/10.1177/030089168907500406.
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The analysis of the molecular mechanisms governing multistep carcinogenesis became experimentally approachable since the identification and characterization in tumor cells of altered or activated versions of cellular genes (oncogenes) that normally control cell growth and differentiation. The activating mutations confer new properties to the oncogene products and should therefore be considered as gain of function mutations. In addition, the oncogenes appear to act as dominant genetic traits since they act also in the presence of the homologous wild-type allele. However, the concept of a dominance of the transformed phenotype has been challenged by early experiments with somatic cell hybrids which showed that the fusion of normal and malignant cells may suppress the tumorigenic phenotype. The suppression or reversion of the malignant phenotype by the introduction of a normal chromosome into a tumor cell line has lent support to the idea that a family of cellular genes are coding for factors capable to interact with the cell-growth control machinery. These genes seem to reconstitute the normal control of cell growth even in the presence of an activated oncogene. In addition, a two-mutation model has been proposed to explain the epidemiological and clinical features of childhood cancers. According to the model, the development of these malignancies can be caused by the loss or inactivation of both alleles of cellular genes, as suggested by the somatic cell hybrid experiments where the function of the inactivated genes is restored by the contribution of those derived from the normal parental cells. This family of genes is designated as onco-suppressor genes since their product is necessary for the normal regulated cell growth and is lacking or inactivated in malignant cells. At gene level they should be considered as recessive genetic traits, since the tumor phenotype appears when both alleles of an oncosuppressor gene are inactivated. The mutations affecting their normal functions belong to the type « loss of function ». The molecular analysis of retinoblastoma has led to the cloning and sequencing of the related onco-suppressor gene (RB gene) whose product displays the features of a gene-regulatory protein. In addition, a binding between the RB product and various viral onco-proteins (E1A, large T, E7) has been demonstrated, thus suggesting a mechanism of RB inactivation by which some DNA viruses can transform the host cell. Finally, the increasing availability of DNA markers, defining restriction fragment length polymorphisms, has led to the mapping of the loci of inherited predisposition for familial cancer syndromes such as MEN-1, VHL and NF-2 and to the extension to common cancers of the allele losses analysis that can reveal onco-suppressor gene inactivation. This indirect approach has suggested the occurrence of different onco-suppressor genes for sporadic breast, colonic and lung cancers, bladder carcinoma, germinal tumors of the testis and malignant melanoma. In particular, colonic cancer provides a significant example of a possible multistep scenario for carcinogenesis in humans in which activated oncogenes (e.g. ras) and inactivated putative onco-suppressor genes (on chromosome 17 and 18) coexist in the same cell.
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Macchini, Marina, Annalisa Astolfi, Valentina Indio, Silvia Vecchiarelli, Elisa Grassi, Carla Serra, Riccardo Casadei, et al. "Whole-transcriptome paired-end sequencing and the pancreatic cancer genetic landscape." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 4048. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.4048.
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4048 Background: A deeper knowledge of the pancreatic cancer (PDAC) biology is needed to improve the prognosis of the disease. Methods: 17 PDAC samples were collected by ultrasound-guided biopsy used for DNA and RNA extraction. 14 samples were analyzed by high resolution copy number analysis (CNA) on Affymetrix SNP array 6.0 and with segmentation algorithm against a reference of 270 Ceu HapMap individuals (Partek Genomic Suite). 17 samples were analyzed by whole transcriptome massively parallel sequencing, performed at 75x2 bp on a HiScanSQ Illumina platform. An average of 7, 3x107 reads per sample were generated, with a mean read depth of 50X. Single nucleotide variants (SNVs) were detected with SNVMix2 and compared with genetic variation databases (dbSNP, 1000genomes, Cosmic). Non-synonimous SNVs were analyzed with the predictors SNPs and GO and PROVEAN. Results: CNA results in 9/14 samples exhibited both macroscopic and cryptic cytogenetic alterations, with a mean of 10 CNA per patient. Most frequent gains were observed in 18q11.2 involving GATA6 (3/14) and 19q13 targeting AKT2 (3/14) while hotspot deletions were found on 18q21 (7/14), 17p13 (6/14), 9p21.3 (6/14), 15q (5/14) and 1q35 (4/14). RNAseq showed that samples exhibited a mean of 145 (range: 61-240) non-synonimous SNVs, of which 16 on average are potentially disease-related. Merging copy number and RNAseq data we highlighted the major oncogenic hits of PDAC, confirming the prevalence (14/17) of KRAS mutations, in one case also NRAS (G13D), and the three oncosuppressor CDKN2A (mutated in 3 cases and deleted in 6 cases, in hetero- or homozygosity), SMAD4 (altered by point mutation or gene deletion in 7/14), and TP53 (lost in 6/14 and mutated in 5/17). The signaling pathways affected were: KRAS/MAPK, TGFbeta and integrin signaling, proliferation and apoptosis, DNA damage response, and epithelial to mesenchymal transition. Moreover we found new oncogenic alterations, such as HMGCR, that displayed mutations in 17% of the analyzed patients (3/17). Conclusions: NGS combined with high resolution cytogenetic analysis can improve the understanding of pancreatic carcinogenesis.
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McConnell, Sean C., Darcy R. Denner, Ashley D. Sample, Anthony C. Restaino, Wilfredo Marin, and Jill L. O. de Jong. "Dichotomous Roles for Hdac1 Haploinsufficiency in T Cell Acute Lymphoblastic Leukemia (T-ALL)." Blood 124, no. 21 (December 6, 2014): 2219. http://dx.doi.org/10.1182/blood.v124.21.2219.2219.
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Abstract Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups from histones and non-histone proteins, thereby modifying the structure of chromatin and regulating gene expression. HDACs have frequently been found to be upregulated in solid tumors and in hematological malignancies, leading to clinical trials of HDAC inhibitors for the treatment of various cancers. Oncogenic effects of HDACs are thought to be mediated by the epigenetic silencing of tumor suppressors. However, understanding of the specific gene targets of individual HDACs is lacking. In order to elucidate the function of HDAC1 in a cancer model, we have performed experiments comparing T cell leukemias in hdac1 haploinsufficient zebrafish with leukemias in their wild type siblings. For our initial studies, we tested whether loss of one allele of the hdac1 gene (haploinsufficiency) would reduce the oncogenic effects of c-Myc, a potent oncogene, and protect against leukemia. We generated T cell lymphoblastic leukemia (T-ALL) in both hdac1+/- haploinsufficient and wild type zebrafish siblings by overexpressing murine c-Myc in T cells using a rag2 promoter. We then monitored the hdac1+/- and wild type fish for tumor incidence, latency, growth and overall survival. The tumor incidence rates and mean latencies were not significantly different for hdac1+/- and wild type tumors. However, we found significant differences in primary tumor growth between these genotypes. Tumor progression was significantly faster for hdac1+/- fish (p=0.001), with mean time to stage 3 tumor (>50% of the animal showing evidence of tumor dissemination) of 43.3 ± 10.1 days (mean ± S.D.) compared with 76.3 ± 9.2 days for wild type siblings. Furthermore, survival of hdac1+/- fish was significantly shorter (p<0.01) at 70.3 ± 36.2 days compared with wild type siblings at 129.2 ± 57.8 days. In contrast, progression of transplanted hdac1+/- tumors was slower compared with transplanted wild type tumors. Only 8.3% of transplanted hdac1+/- tumors had extended into the thymus and other organs by 21 days following intra-peritoneal injection into recipients. In contrast, 92% of the wild type tumors had evidence of widespread tumor dissemination by 21 days post-transplant. Several mechanisms were considered as potential contributing factors to these differences between the hdac +/- and wild type leukemias, including cell cycle differences, the effects of different tumor micro-environments, and differences in leukemia-initiating cell (LIC) frequencies. We did not find obvious differences in cell cycle parameters between genotypes. Also, we found no effect from different microenvironments of tumors following transplantation into either hdac1 +/- or wild type recipients. In contrast, we did find significant differences in leukemia-initiating cell frequencies between the genotypes (p<0.0001). The LIC frequency for hdac1 +/- tumors was measured at 1 in 410 compared with a higher LIC frequency of 1 in 30 for wild type tumors. In summary, our data provide support for dual roles of hdac1 in leukemogenesis. In this model, hdac1 has an initial protective role acting as an oncosuppressor, leading to more rapid tumor progression and decreased survival of animals with hdac1 +/- haploinsufficient tumors compared with wild type tumors. Interestingly, hdac1 also behaved as an oncogene, with decreased tumor progression following transplantation of hdac1 haploinsufficient tumors compared with wild type tumors. Our data indicate that caution is warranted regarding the use of HDAC inhibitors in treating hematologic malignancy, as this treatment could have unintended consequences, particularly during early stages of tumor development. Explaining these apparently contradictory roles of hdac1 in leukemogenesis is the focus of ongoing investigation, including gene expression studies and validation of targets. Disclosures No relevant conflicts of interest to declare.
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Valeri, Nicola, Chiara Braconi, Pierluigi Gasparini, Sergei Grivennikow, Jonathan R. Hart, Alessio Paone, Francesca Lovat, et al. "Anti-miR-135b in colon cancer treatment: Results from a preclinical study." Journal of Clinical Oncology 30, no. 4_suppl (February 1, 2012): 457. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.457.
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457 Background: MicroRNAs (miRs) are small non coding RNAs involved in cell homeostasis. miRs are deregulated in colorectal cancer (CRC). Our study aimed at identifying miRs with a driver role in carcinogenesis altered by similar mechanisms in both human and mouse CRC. Goal of the study was to use CRC mouse models for the pre-clinical development of anti-miRs as therapeutic drugs. Methods: Azoximetane (AOM)/Dextran-Sulfate (DSS) treated mice or CDX2-CRE/APC-/- mice were used to study inflammation-associated and sporadic APC-related CRC. Human Inflammatory Bowel Disease associated (n=30), and sporadic (n=90) CRC with their matched normal tissues were collected according to Good Clinical Practice recommendation and subjected to RNA extraction using Trizol. miR and gene expression profiling was assessed by nCounter technology (Nanostring Seattle). Anti-miR-135b and scrambled probes for in vivo studies were synthesized by Girindus. Results: miRs profiling from AOM/DSS and CDX2-CRE/APC-/- CRC. revealed that miR-135b is one of the most up-regulated miRs in both models. In humans miR-135b over-expression was found in both IBD and sporadic CRC and was associated with reduced Progression Free Survival and Overall Survival in CRC patients. Molecular studies in Mouse Embryo Fibroblast and human CRC cell lines highlighted the role of two major pathways in the upstream activation of miR-135b: APC-β-Catenin and SRC-PI3K. MiR-135b up-regulation resulted in reduced apoptosis and increased invasion and metastasis due to the down-regulation of TGFRB2, DAPK1, APC and HIF1AN. Silencing of miR-135b in vivo reduced tumor multiplicity and tumor load in the AOM/DSS CRC model. Mice treated with anti-miR-135b showed well differentiated tumors and microacinar pattern while tumors in the control groups showed low differentiation and adenomatous pattern. Conclusions: Our data suggest that miR-135b is a key molecule whose activation is downstream of oncogenes and oncosuppressor genes frequently altered in CRC. Our study defines specific pathways that converge on the activation of the same microrna. The “in vivo” silencing of miR-135 shows preclinical efficacy with low toxicity and represents the first in vivo study for the use of antimiRs in CRC treatment.
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Branchi, F., C. Heldt, B. Siegmund, and M. Schumann. "DOP51 Investigation on the role of Par4-associated cell polarity and associated barrier defects in inflammatory bowel diseases." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S089. http://dx.doi.org/10.1093/ecco-jcc/jjz203.090.
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Abstract Background In inflammatory bowel diseases (IBD), epithelial barrier defects occur as a consequence of chronic inflammation. Recent research suggested that cell polarity alterations may be upstream of barrier defects and additionally play a role in IBD-associated carcinogenesis (colitis-associated and small intestinal carcinoma). Par4 is a gene encoding a protein crucial in the development of cell polarity. LKB1, its human homologue, is mutated in Peutz–Jeghers syndrome (PJS), a genetic condition characterised by a higher risk of epithelial cancers. While the pivotal role of Par4/LKB1 in the development of epithelial cell polarity is established, its involvement in IBD-associated barrier defects and carcinogenesis is yet to be defined. Methods Endoscopic bowel mucosa samples from patients with Crohn’s disease, ulcerative colitis, PJS and controls were analysed to assess expression and localisation of Par4/LKB1. Cryosections were immunostained for Par4/LKB-1 along with a diverse set of markers of cell polarity and intercellular adhesion. The analysis was performed by confocal laser scanning microscopy in order to compare the expression of mucosal as well as the subcellular localisation of Par4/LKB1 in the gut mucosa. A quantitative analysis of protein expression with western blotting was performed as well. The function of Par4/LKB1 in intestinal epithelial cells (IEC) was evaluated by means of a Par4-deficient IEC model as well as in an IEC Par4-overexpression model. Moreover, a preliminary assessment of the possible role of Par4/LKB1-related polarity processes in IBD-associated carcinomas was performed through scanning genetic data from colitis-associated carcinomas for potential Par4-related mutations and altered Par4/LKB1 expression. Results The immunofluorescent staining allowed visualisation of intracellular expression of Par4 in epithelia from PJS, IBD patients and controls. In PJS-polyps, despite the alteration of regular tissue architecture typical of these lesions, the polarity of epithelial cells was maintained - contrary to control tissue, a punctate pattern of the Par4 staining was shown. In IBD tissue, no relevant differences in Par4 expression at confocal microscopy, as well as a quantitative assessment, were observed as compared with controls. No differences were observed in PJS or IBD samples as regards the expression of cell polarity markers such as Par3, CD71, crb3 or adhesion molecules such as ZO-1, e-cadherin, occludin, JAM-A. As regards the IEC model, we observed that Caco-2/BBe cells overexpressing Par4/LKB1 showed enhanced Par4/LKB1 cytosolic staining at immunofluorescence. In this model, a defective epithelial polarity and organisation on permeable supports could be observed in Caco2/BBe cysts in parallel with reduced expression of native LKB1 as seen in western blots. Preliminary analysis of data from our colitis-associated carcinomas database suggested various pathways potentially involving Par4/LKB1, yet no direct analysis of tissue samples for Par4-related mutations was performed yet. Conclusions Altered expression of Par4 in epithelial cells may influence the development of a functional epithelial barrier as suggested by IEC models. Par4/LKB1 as a known oncosuppressor gene is involved in a number of pathways potentially relevant for carcinogenesis in IBD; however, a direct connection between Par4-related alteration of the epithelial barrier and carcinogenesis is yet to be established.
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Pighi, Chiara, Mara Compagno, Qi Wang, Taek-Chin Cheong, Teresa Poggio, Fernanda Langellotto, Paola Francia di Celle, Alberto Zamò, and Roberto Chiarle. "FBXO11, a Regulator of BCL6 Stability, Is Recurrently Mutated in Burkitt Lymphoma." Blood 126, no. 23 (December 3, 2015): 3673. http://dx.doi.org/10.1182/blood.v126.23.3673.3673.
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Abstract INTRODUCTION: We recently described inactivating mutations of the FBXO11 gene in Diffuse Large B Cell Lymphoma (DLBCL). One major function of FBXO11 is to regulate BCL6 stability as well as other targets such as SNAIL. BCL6 acts as an oncogene in several human B-cell lymphomas and its expression levels can be increased by several mechanisms including chromosomal translocations, point mutations in the promoter region and reduced degradation by inactivation of FBXO11. Thus, FBXO11 acts as an oncosuppressor in DLBCL by promoting the accumulation of BCL6. However, a clear and complete picture of the distribution of FBXO11 mutations in different lymphoma subtypes is missing, and the in vivo functions of FBXO11 in normal tissue and lymphoma development are completely lacking. In the present work, we investigated the frequency and distribution of FBXO11 mutations in an extended panel of human BCL6 positive lymphoma and we functionally validated novel FBXO11 mutations for their ability to induce BCL6 degradation. METHODS: We sequenced the entire FBXO11 coding sequence by classical Sanger sequencing in 100 cases of Follicular Lymphoma (FL), 36 cases of Burkitt Lymphoma (BL), 8 BL cell lines and 8 Anaplastic Large cell lymphoma (ALCL) cell lines, which are typically BCL6-positive lymphomas. Moreover, we sequenced 50 cases of Marginal Zone B cell Lymphoma (MZL), which show variable expression of BCL6. To investigate whether the FBXO11 mutations interfere with FBXO11 activity we generated complementary DNA constructs containing these mutations. Wild-type FBXO11 or FBXO11 mutants were expressed in HEK-293T cells with constructs expressing BCL6 or SNAIL. Twenty-four hours after transfection, HEK-293T cells were treated with cycloheximide and harvested at different time points to check substrates expression and degradation by immunoblotting. RESULTS: BL carried the highest frequency of FBXO11 mutations (12/44 cases analyzed, 27%), whereas FL and MZL were very rarely affected by FBXO11 mutations (1/100 FL and 1/50 MZL). The analysis identified several mutations, either located in the coding sequence mostly in the CASH (functional) domains or located in intronic sequences controlling exon splicing. Sequence changes included missense mutations (n=8), deletions (n=2), a frameshift deletion introducing a premature stop codon (n=1) and nucleotide substitutions at consensus splice donor sites (n=2) and acceptor site (n=1). Remarkably, these last mutations represent the first report of splice site mutations affecting the FBXO11 gene. By cDNA amplification and sequencing, we demonstrated skipping of entire exons: the splice site mutations located at the donor site of exon 15 and 19 lead to the loss of the exon 15 and 19 respectively, while the splice site mutation affecting the acceptor site of exon 16 results in the deletion of the adjacent exon 16. Two of the point mutations (K631N and Y122C), affecting one case of FL and MZL respectively, were also found in the previous panel of DLBCLs (Duan et al, Nature 2012). Both cases consisted of a low grade component adjacent to an area of high grade transformation. By microdissection, we separately studied the two components of each of these cases to demonstrate that the mutation was present only in the high grade component. Finally, to validate all the mutations found in BL, we generated mutant constructs corresponding to each of them. By this approach, we showed that all the mutations identified are loss of function variants because they impaired the FBXO11 ability to promote BCL6 and SNAIL degradation. CONCLUSIONS: We identified several FBXO11 novel mutations in a large panel of BCL6-positive human lymphomas. All the mutations identified were inactivating the FBXO11 ability to induce BCL6 and SNAIL degradation. In contrast, mutations of FBXO11 are rare in low grade FL and MZL and, when present, are associated with high grade transformation. Together with our previous findings, this study showed that FBXO11 is mostly mutated in aggressive lymphomas such as DLBCL and BL, thus suggesting that FBXO11 mutations could contribute to the de-novo onset or transformation into high grade lymphoma. Disclosures No relevant conflicts of interest to declare.
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Rubino, Marcello, Paolo Kunderfranco, Gianluca Basso, Carolina Magdalen Greco, Fabio Pasqualini, Simone Serio, Massimo Roncalli, et al. "Epigenetic regulation of the extrinsic oncosuppressor PTX3 gene in inflammation and cancer." OncoImmunology, May 30, 2017, e1333215. http://dx.doi.org/10.1080/2162402x.2017.1333215.
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Polato, Federica, Paolo Rusconi, Stefano Zangrossi, Federica Morelli, Mattia Boeri, Alberto Musi, Sergio Marchini, et al. "DRAGO (KIAA0247), a New DNA Damage–Responsive, p53-Inducible Gene That Cooperates With p53 as Oncosuppressor." JNCI: Journal of the National Cancer Institute 106, no. 4 (March 20, 2014). http://dx.doi.org/10.1093/jnci/dju053.
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Chasov, Vitaly, Mikhail Zaripov, Regina Mirgayazova, Raniya Khadiullina, Ekaterina Zmievskaya, Irina Ganeeva, Aigul Valiullina, Albert Rizvanov, and Emil Bulatov. "Promising New Tools for Targeting p53 Mutant Cancers: Humoral and Cell-Based Immunotherapies." Frontiers in Immunology 12 (August 13, 2021). http://dx.doi.org/10.3389/fimmu.2021.707734.
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Transcription factor and oncosuppressor protein p53 is considered as one of the most promising molecular targets that remains a high-hanging fruit in cancer therapy. TP53 gene encoding the p53 protein is known to be the most frequently mutated gene in human cancers. The loss of transcriptional functions caused by mutations in p53 protein leads to deactivation of intrinsic tumor suppressive responses associated with wild-type (WT) p53 and acquisition of new pro-oncogenic properties such as enhanced cell proliferation, metastasis and chemoresistance. Hotspot mutations of p53 are often immunogenic and elicit intratumoral T cell responses to mutant p53 neoantigens, thus suggesting this protein as an attractive candidate for targeted anti-cancer immunotherapies. In this review we discuss the possible use of p53 antigens as molecular targets in immunotherapy, including the application of T cell receptor mimic (TCRm) monoclonal antibodies (mAbs) as a novel powerful approach.
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Romero-García, Raquel, Laura Gómez-Jaramillo, Rosa María Mateos, Gema Jiménez-Gómez, Nuria Pedreño-Horrillo, Esther Foncubierta, Juan Francisco Rodríguez-Gutiérrez, et al. "Differential epigenetic regulation between the alternative promoters, PRDM1α and PRDM1β, of the tumour suppressor gene PRDM1 in human multiple myeloma cells." Scientific Reports 10, no. 1 (September 28, 2020). http://dx.doi.org/10.1038/s41598-020-72946-z.
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Abstract Multiple myeloma (MM) is a B-cell neoplasm that is characterized by the accumulation of malignant plasma cells in the bone marrow. The transcription factor PRDM1 is a master regulator of plasma cell development and is considered to be an oncosuppressor in several lymphoid neoplasms. The PRDM1β isoform is an alternative promoter of the PRDM1 gene that may interfere with the normal role of the PRDM1α isoform. To explain the induction of the PRDM1β isoform in MM and to offer potential therapeutic strategies to modulate its expression, we characterized the cis regulatory elements and epigenetic status of its promoter. We observed unexpected patterns of hypermethylation and hypomethylation at the PRDM1α and PRDM1β promoters, respectively, and prominent H3K4me1 and H3K9me2 enrichment at the PRDM1β promoter in non-expressing cell lines compared to PRDM1β-expressing cell lines. After treatment with drugs that inhibit DNA methylation, we were able to modify the activity of the PRDM1β promoter but not that of the PRDM1α promoter. Epigenetic drugs may offer the ability to control the expression of the PRDM1α/PRDM1β promoters as components of novel therapeutic approaches.
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Annese, Tiziana, Roberto Tamma, Michelina De Giorgis, and Domenico Ribatti. "microRNAs Biogenesis, Functions and Role in Tumor Angiogenesis." Frontiers in Oncology 10 (November 27, 2020). http://dx.doi.org/10.3389/fonc.2020.581007.
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microRNAs (miRNAs) are small non-coding RNA molecules, evolutionary conserved. They target more than one mRNAs, thus influencing multiple molecular pathways, but also mRNAs may bind to a variety of miRNAs, either simultaneously or in a context-dependent manner. miRNAs biogenesis, including miRNA transcription, processing by Drosha and Dicer, transportation, RISC biding, and miRNA decay, are finely controlled in space and time.miRNAs are critical regulators in various biological processes, such as differentiation, proliferation, apoptosis, and development in both health and disease. Their dysregulation is involved in tumor initiation and progression. In tumors, they can act as onco-miRNAs or oncosuppressor-miRNA participating in distinct cellular pathways, and the same miRNA can perform both activities depending on the context.In tumor progression, the angiogenic switch is fundamental. miRNAs derived from tumor cells, endothelial cells, and cells of the surrounding microenvironment regulate tumor angiogenesis, acting as pro-angiomiR or anti-angiomiR.In this review, we described miRNA biogenesis and function, and we update the non-classical aspects of them. The most recent role in the nucleus, as transcriptional gene regulators and the different mechanisms by which they could be dysregulated, in tumor initiation and progression, are treated. In particular, we describe the role of miRNAs in sprouting angiogenesis, vessel co-option, and vasculogenic mimicry. The role of miRNAs in lymphoma angiogenesis is also discussed despite the scarcity of data.The information presented in this review reveals the need to do much more to discover the complete miRNA network regulating angiogenesis, not only using high-throughput computational analysis approaches but also morphological ones.
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Angrisani, Annapaola, Annamaria Di Fiore, Claudia Augusta Di Trani, Simone Fonte, Marialaura Petroni, Ludovica Lospinoso Severini, Fabio Bordin, et al. "Specific Protein 1 and p53 Interplay Modulates the Expression of the KCTD-Containing Cullin3 Adaptor Suppressor of Hedgehog 2." Frontiers in Cell and Developmental Biology 9 (April 8, 2021). http://dx.doi.org/10.3389/fcell.2021.638508.
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The Hedgehog (Hh) signaling pathway plays a crucial role in normal embryonic development and adult tissue homeostasis. On the other end, dysregulated Hh signaling triggers a prolonged mitogenic response that may prompt abnormal cell proliferation, favoring tumorigenesis. Indeed, about 30% of medulloblastomas (MBs), the most common malignant childhood cerebellar tumors, exhibit improper activation of the Hh signaling. The oncosuppressor KCASH2 has been described as a suppressor of the Hh signaling pathway, and low KCASH2 expression was observed in Hh-dependent MB tumor. Therefore, the study of the modulation of KCASH2 expression may provide fundamental information for the development of new therapeutic approaches, aimed to restore physiological KCASH2 levels and Hh inhibition. To this end, we have analyzed the TATA-less KCASH2 proximal promoter and identified key transcriptional regulators of this gene: Sp1, a TF frequently overexpressed in tumors, and the tumor suppressor p53. Here, we show that in WT cells, Sp1 binds KCASH2 promoter on several putative binding sites, leading to increase in KCASH2 expression. On the other hand, p53 is involved in negative regulation of KCASH2. In this context, the balance between p53 and Sp1 expression, and the interplay between these two proteins determine whether Sp1 acts as an activator or a repressor of KCASH2 transcription. Indeed, in p53–/– MEF and p53 mutated tumor cells, we hypothesize that Sp1 drives promoter methylation through increased expression of the DNA methyltransferase 1 (DNMT1) and reduces KCASH2 transcription, which can be reversed by Sp1 inhibition or use of demethylating agents. We suggest therefore that downregulation of KCASH2 expression in tumors could be mediated by gain of Sp1 activity and epigenetic silencing events in cells where p53 functionality is lost. This work may open new venues for novel therapeutic multidrug approaches in the treatment of Hh-dependent tumors carrying p53 deficiency.
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Porzionato, A., M. Rucinski, V. Macchi, G. Sarasin, L. K. Malendowicz, and R. De Caro. "ECRG4 expression in normal rat tissues: expression study and literature review." European Journal of Histochemistry 59, no. 2 (May 18, 2015). http://dx.doi.org/10.4081/ejh.2015.2458.
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The <em>Esophageal Cancer Related Gene 4</em> (<em>ECRG4</em>) is a highly conserved tumour suppressor gene encoding various peptides (augurin, CΔ16 augurin, ecilin, argilin, CΔ16 argilin) which can be processed and secreted. In the present work, we examined <em>ECRG4</em> expression and location in a wide range of rat organs and reviewed the available literature. <em>ECRG4</em> mRNA was identified in all examined tissues by quantitative PCR (qPCR). <em>ECRG4</em> immunoreaction was mainly cytoplasmic, and was detected in heart and skeletal muscles, smooth muscle cells showing only weak reactions. In the digestive system, <em>ECRG4</em> immunostaining was stronger in the esophageal epithelium, bases of gastric glands, hepatocytes and pancreatic acinar epithelium. In the lymphatic system, immunoreactive cells were detectable in the thymus cortex, lymph node medulla and splenic red pulp. In the central and peripheral nervous systems, different neuronal groups showed different reaction intensities. In the endocrine system, <em>ECRG4</em> immunoreaction was detected in the hypothalamic paraventricular and supraoptic nuclei, hypophysis, thyroid and parathyroid glands, adrenal <em>zona glomerularis</em> and medulla and Leydig cells, as well as in follicular and luteal cells of the ovary. In the literature, ECRG4 has been reported to inhibit cell proliferation and increase apoptosis in various cell types. It is down-regulated, frequently due to hypermethylation, in esophageal, prostate, breast and colon cancers, together with glioma (oncosuppressor function), although it is up-regulated in papillary thyroid cancer (oncogenic role). <em>ECRG4</em> expression is also higher in non-proliferating cells of the lymphatic system. In conclusion, our identification of <em>ECRG4</em> in many structures suggests the involvement of <em>ECRG4</em> in the tumorigenesis of other organs and also the need for further research. In addition, on the basis of the location of <em>ECRG4</em> in neurons and endocrine cells and the fact that it can be secreted, its role as a neurotransmitter/neuromodulator and endocrine factor must be examined in depth in the future.