Journal articles on the topic 'Hepatocellular cancer, p21, p53'
To see the other types of publications on this topic, follow the link: Hepatocellular cancer, p21, p53.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Hepatocellular cancer, p21, p53.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Wang, Juan, Yuan Zhou, Chunyan Gu, Fang Ming, and Ying Zhang. "LncRNA SAMD12-AS1 Suppresses Proliferation and Migration of Hepatocellular Carcinoma via p53 Signaling Pathway." Journal of Oncology 2022 (August 23, 2022): 1–9. http://dx.doi.org/10.1155/2022/9096365.
Full textAbstract:
Purpose. Assessment of lncRNA SAMD12-AS1 expression in liver cancer tissues and cell lines to investigate the underlying molecular mechanisms that regulate liver cancer cell growth, development, invasion, and migration. Methods. The lncRNA SAMD12-AS1 expression in tumor tissues of 32 liver cancer patients was measured by real-time PCR, and its effect on the clinicopathological manifestations and liver cancer patients’ prognosis was determined. LncRNA SAMD12-AS1 overexpression and knockdown in liver cancer cell lines were established by cell transfection. The effects of lncRNA SAMD12-AS1 knockdown and overexpression on liver cancer cell growth, development, invasion, and migration were determined by MTT, Transwell, and clonogenic assays. Furthermore, its effects on the expression of E-cadherin, vimentin, p53, and p21 in hepatocellular carcinoma cells were determined by Western blot assay. Results. The level of lncRNA SAMD12-AS1 expression in tumor tissues was remarkably higher than that in paracancerous liver tissues ( p < 0.01 ). It was found that the lncRNA SAMD12-AS1 expression was largely correlated with TNM stage of tumor, vascular invasion, and hepatitis B surface (HBs) antigen in liver cancer patients ( p < 0.05 ). Cell function experiments showed that lncRNA SAMD12-AS1 overexpression promoted liver cancer development, migration, and invasion ( p < 0.05 ), while lncRNA SAMD12-AS1 knockdown inhibited the activity of liver cancer cells to invade and migrate ( p < 0.05 ). Western blot analysis showed that overexpression of lncRNA SAMD12-AS1 markedly inhibited p21, p53, and E-cadherin expression and promoted vimentin expression. Conversely, knockdown of lncRNA SAMD12-AS1 significantly promoted p21, p53, and E-cadherin expression and inhibited vimentin expression ( p < 0.05 ). Conclusion. LncRNA SAMD12-AS1 is associated with the TNM stage and vascular invasion of liver cancer. It promotes liver cancer cell development, invasion, and migration by regulating p53 expression. Thus, lncRNA SAMD12-AS1 could be a novel biological target for the treatment of liver cancer.
2
Qin, Lan Fang, Irene O. L. Ng, Sheung T. Fan, and Matthew Ng. "p21/WAF1, p53 and PCNA expression andp53 mutation status in hepatocellular carcinoma." International Journal of Cancer 79, no. 4 (August 21, 1998): 424–28. http://dx.doi.org/10.1002/(sici)1097-0215(19980821)79:4<424::aid-ijc19>3.0.co;2-4.
Full text
3
Zhang, Erlei, and Zhiyong Huang. "XRCC2 promotes cancer progression by regulating p53/p21 signaling pathway in hepatocellular carcinoma." HPB 21 (2019): S358—S359. http://dx.doi.org/10.1016/j.hpb.2019.10.1974.
Full text
4
Zhang, E., Z. Huang, and X. Chen. "XRCC2 promotes cancer progression by regulating p53/p21 signaling pathway in hepatocellular carcinoma." HPB 20 (September 2018): S408—S409. http://dx.doi.org/10.1016/j.hpb.2018.06.2739.
Full text
5
Huang, Jhen-Yu, You-Cian Lin, Han-Min Chen, Jiun-Tsai Lin, and Shao-Hsuan Kao. "Adenine Combined with Cisplatin Promotes Anticancer Activity against Hepatocellular Cancer Cells through AMPK-Mediated p53/p21 and p38 MAPK Cascades." Pharmaceuticals 15, no. 7 (June 26, 2022): 795. http://dx.doi.org/10.3390/ph15070795.
Full textAbstract:
Cisplatin has been widely used in cancer treatments. Recent evidence indicates that adenine has potential anticancer activities against various types of cancers. However, the effects of the combination of adenine and cisplatin on hepatocellular carcinoma (HCC) cells remain sketchy. Here, our objective was to elucidate the anticancer activity of adenine in combination with cisplatin in HCC cells and its mechanistic pathways. Cell viability and cell cycle progression were assessed by the SRB assay and flow cytometry, respectively. Apoptosis was demonstrated by PI/annexin V staining and flow cytometric analysis. Protein expression, signaling cascade, and mRNA expression were analyzed by Western blotting and quantitative RT-PCR, respectively. Our results showed that adenine jointly potentiated the inhibitory effects of cisplatin on the cell viability of SK-Hep1 and Huh7 cells. Further investigation showed that adenine combined with cisplatin induced higher S phase arrest and apoptosis in HCC cells. Mechanically, adenine induced AMPK activation, reduced mTOR phosphorylation, and increased p53 and p21 levels. The combination of adenine and cisplatin synergistically reduced Bcl-2 and increased PUMA, cleaved caspase-3, and PARP in HCC cells. Adenine also upregulated the mRNA expression of p53, p21, PUMA, and PARP, while knockdown of AMPK reduced the increased expression of these genes. Furthermore, adenine also induced the activation of p38 MAPK through AMPK signaling, and the inhibition of p38 MAPK reduced the apoptosis of HCC cells with exposure to adenine combined with cisplatin. Collectively, these findings reveal that the combination of adenine and cisplatin synergistically enhances apoptosis of HCC cells, which may be attributed to the AMPK-mediated p53/p21 and p38 MAPK cascades. It suggests that adenine may be a potential adjuvant for the treatment of HCC in combination with cisplatin.
6
Wan, Xin-xing, Han-chun Chen, Md Asaduzzaman Khan, Ai-hua Xu, Fu-lan Yang, Yun-yi Zhang, and Dian-zheng Zhang. "ISG15 Inhibits IFN-α-Resistant Liver Cancer Cell Growth." BioMed Research International 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/570909.
Full textAbstract:
Hepatocellular carcinoma (HCC) is one of the most prevalent tumors worldwide. Interferon-α(IFN-α) has been widely used in the treatment of HCC, but patients eventually develop resistance. ISG15 ubiquitin-like modifier (ISG15) is a ubiquitin-like protein transcriptionally regulated by IFN-αwhich shows antivirus and antitumor activities. However, the exact role of ISG15 is unknown. In the present study, we showed that IFN-αsignificantly induced ISG15 expression but failed to induce HepG2 cell apoptosis, whereas transient overexpression of ISG15 dramatically increased HepG2 cell apoptosis. ISG15 overexpression increased overall protein ubiquitination, which was not observed in cells with IFN-α-induced ISG15 expression, suggesting that IFN-αtreatment not only induced the expression of ISG15 but also inhibited ISG15-mediated ubiquitination. The tumor suppressor p53 and p21 proteins are the key regulators of cell survival and death in response to stress signals such as DNA damage. We showed that p53 or p21 is only up regulated in HepG2 cells ectopically expressing ISG15, but not in the presence of IFN-α-induced ISG15. Our results suggest that ISG15 overexpression could be developed into a powerful gene-therapeutic tool for treating IFN-α-resistant HCC.
7
Park, So Hyun, Ji-Young Hong, Hyen Joo Park, and Sang Kook Lee. "The Antiproliferative Activity of Oxypeucedanin via Induction of G2/M Phase Cell Cycle Arrest and p53-Dependent MDM2/p21 Expression in Human Hepatoma Cells." Molecules 25, no. 3 (January 23, 2020): 501. http://dx.doi.org/10.3390/molecules25030501.
Full textAbstract:
Oxypeucedanin (OPD), a furocoumarin compound from Angelica dahurica (Umbelliferae), exhibits potential antiproliferative activities in human cancer cells. However, the underlying molecular mechanisms of OPD as an anticancer agent in human hepatocellular cancer cells have not been fully elucidated. Therefore, the present study investigated the antiproliferative effect of OPD in SK-Hep-1 human hepatoma cells. OPD effectively inhibited the growth of SK-Hep-1 cells. Flow cytometric analysis revealed that OPD was able to induce G2/M phase cell cycle arrest in cells. The G2/M phase cell cycle arrest by OPD was associated with the downregulation of the checkpoint proteins cyclin B1, cyclin E, cdc2, and cdc25c, and the up-regulation of p-chk1 (Ser345) expression. The growth-inhibitory activity of OPD against hepatoma cells was found to be p53-dependent. The p53-expressing cells (SK-Hep-1 and HepG2) were sensitive, but p53-null cells (Hep3B) were insensitive to the antiproliferative activity of OPD. OPD also activated the expression of p53, and thus leading to the induction of MDM2 and p21, which indicates that the antiproliferative activity of OPD is in part correlated with the modulation of p53 in cancer cells. In addition, the combination of OPD with gemcitabine showed synergistic growth-inhibitory activity in SK-Hep-1 cells. These findings suggest that the anti-proliferative activity of OPD may be highly associated with the induction of G2/M phase cell cycle arrest and upregulation of the p53/MDM2/p21 axis in SK-HEP-1 hepatoma cells.
8
Lin, Yi-Ting, Shu-Man Liang, Ya-Ju Wu, Yi-Ju Wu, Yi-Jhu Lu, Yee-Jee Jan, Bor-Sheng Ko, et al. "Cordycepin Suppresses Endothelial Cell Proliferation, Migration, Angiogenesis, and Tumor Growth by Regulating Focal Adhesion Kinase and p53." Cancers 11, no. 2 (February 1, 2019): 168. http://dx.doi.org/10.3390/cancers11020168.
Full textAbstract:
Focal adhesion kinase (FAK) plays an important role in vascular development, including the regulation of endothelial cell (EC) adhesion, migration, proliferation, and survival. 3’-deoxyadenosine (cordycepin) is known to suppress FAK expression, cell migration, and the epithelial–mesenchymal transition in hepatocellular carcinoma (HCC). However, whether cordycepin affects FAK expression and cellular functions in ECs and the specific molecular mechanism remain unclear. In this study, we found that cordycepin suppressed FAK expression and the phosphorylation of FAK (p-FAK) at Tyr397 in ECs. Cordycepin inhibited the proliferation, wound healing, transwell migration, and tube formation of ECs. Confocal microscopy revealed that cordycepin significantly reduced FAK expression and decreased focal adhesion number of ECs. The suppressed expression of FAK was accompanied by induced p53 and p21 expression in ECs. Finally, we demonstrated that cordycepin suppressed angiogenesis in an in vivo angiogenesis assay and reduced HCC tumor growth in a xenograft nude mice model. Our study indicated that cordycepin could attenuate cell proliferation and migration and may result in the impairment of the angiogenesis process and tumor growth via downregulation of FAK and induction of p53 and p21 in ECs. Therefore, cordycepin may be used as a potential adjuvant for cancer therapy.
9
Abou-Alfa, G. K., R. D. Carvajal, K. Y. Chung, R. A. Ghossein, M. Capanu, M. Gonen, G. Jacobs, D. P. Kelsen, and G. K. Schwartz. "A non-randomized phase II study of sequential irinotecan (CPT) and flavopiridol (F) in patients (pts) with advanced hepatocellular carcinoma (HCC)." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 4148. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.4148.
Full textAbstract:
4148 Background: F is a CDK inhibitor which potentiates CPT- induced apoptosis. In a phase I trial of CPT 100mg/m2 followed 7 hours later by F given over 1 hour weekly for 4 out of 6 weeks (Shah, Clin Can Res 2005), 2 pts with advanced HCC had stable disease (SD) for 14+ months. In the same phase I study, patients who were p53 wild-type (negative p53 staining), and whose p21 remained stable or was non-detectable on the post-treatment biopsy, were noted to have SD or a partial response. Methods: Pts with advanced HCC, no prior systemic therapy, Child’s-Pugh score A, B7 or B8, and KPS ≥ 70%, received 100 mg/m2 of CPT, followed 7 hours later by 60 mg/m2 of F over 1 hour weekly for 4 out of 6 weeks. The trial had a two stage design, with a planned accrual of 30 pts. The primary endpoint was TTP. Tumor response was assessed every 2 cycles using revised WHO criteria. p53 immuno-staining was performed on pre-treatment paraffin preserved tissues. A cut-off of 20% defined positive mutant versus negative wild-type p53 status. Results: 16 pts were enrolled: median age 64 (range 26–84), KPS 80% (70–90%), and 10 males/6 females. 13 pts received therapy, two progressed before starting, and one patient (pt) was excluded because pathology re-review did not confirm HCC. 1 pt was excluded because of consent withdrawal after first dose of therapy. This pt was included in the toxicity analysis. The median number of cycles given was 2 (range 1–8 cycles). Grade 3 and 4 toxicities included dehydration (4: 30%) diarrhea (2: 15%) febrile neutropenia (6: 46% - 4 events in one pt) and fatigue/weakness (3: 23%). Therapy had to be discontinued in 2 pts because of toxicity. TTP was 2.6 months (95% CI 2.43–8.42). One patient had SD for over a year, 8 had progression of disease (POD), and 4 came off study because of toxicity. Mutational p53 was evaluated in 7 pts. The pt with SD had wild type p53. Three pts with POD had mutant p53, while the other 3 had wild type 53. Conclusions: CPT followed by F is an ineffective therapy for HCC. This therapy was relatively poorly tolerated, likely contributed to by underlying cirrhosis in HCC, but similar to our experience of CPT in HCC. While p21 level pre and post therapy is lacking, the wild type p53 of the patient with SD maybe a predictor of response in HCC where p53 mutations are common. No significant financial relationships to disclose.
10
Yang, Taewoo, Yegyun Choi, Jae Won Joh, Steve K. Cho, Dae-Shick Kim, and Sung-Gyoo Park. "Phosphorylation of p53 Serine 15 Is a Predictor of Survival for Patients with Hepatocellular Carcinoma." Canadian Journal of Gastroenterology and Hepatology 2019 (February 7, 2019): 1–8. http://dx.doi.org/10.1155/2019/9015453.
Full textAbstract:
Background. Hepatocellular carcinoma (HCC) is one of the most common malignant cancers with a poor prognosis. Several commonly investigated immunohistochemical markers in resected HCC have potential prognostic value, but the prognostic utility of p53 expression in HCC has remained elusive. Aim. To evaluate the prognostic value of p53 and p53 phosphorylation at serine 15 (p53 Ser15-P) in patients with HCC. Methods. Surgically resected tumors from 199 HCC patients were analyzed for p21, p53, p53 Ser15-P, and proliferating cell nuclear antigen (PCNA) expression using immunohistochemistry. Results. Stratifying by the expression of p53 Ser15-P (P = 0.016), but not by p53 (P = 0.301), revealed significantly different survival outcomes in patients with HCC. Moreover, our analysis demonstrated that patients who were PCNA-positive and p53 Ser15-P–negative had significantly worse survival outcomes (P = 0.001) than patients who were PCNA-positive and p53 Ser15-P–positive. Conclusions. P53 Ser15-P is associated with poor outcomes in patients with HCC, and this prognostic marker is useful for predicting the survival of patients with PCNA-positive HCC.
11
Zhang, Lingyun, Yufeng He, Ximing Wu, Guangshan Zhao, Ke Zhang, Chung S. Yang, Russel J. Reiter, and Jinsong Zhang. "Melatonin and (−)-Epigallocatechin-3-Gallate: Partners in Fighting Cancer." Cells 8, no. 7 (July 19, 2019): 745. http://dx.doi.org/10.3390/cells8070745.
Full textAbstract:
We have demonstrated previously that melatonin attenuates hepatotoxicity triggered by high doses of (−)-epigallocatechin-3-gallate (EGCG) in mice. The current work investigated the influence of melatonin on the oncostatic activity of EGCG in two cancer cell lines, wherein melatonin induced an opposite response of p21. In human tongue cancer TCA8113 cells, melatonin-induced p21 and EGCG-mediated formation of quinoproteins were positively associated with the oncostatic effects of melatonin and EGCG. Melatonin-stimulated an increase in p21 which was correlated with a pronounced nuclear translocation of thioredoxin 1 and thioredoxin reductase 1, both of which are known to induce p21 via promoting p53 trans-activation. Melatonin did not influence the EGCG-mediated increase of quinoprotein formation nor did EGCG impair melatonin-induced p21 up-regulation. Co-treatment with both agents enhanced the cell-killing effect as well as the inhibitory activities against cell migration and colony formation. It is known that p21 also plays a powerful anti-apoptotic role in some cancer cells and confers these cells with a survival advantage, making it a target for therapeutic suppression. In human hepatocellular carcinoma HepG2 cells, melatonin suppressed p21 along with the induction of pro-survival proteins, PI3K and COX-2. However, EGCG prevented against melatonin-induced PI3K and COX-2, and melatonin probably sensitized HepG2 cells to EGCG cytotoxicity via down-regulating p21, Moreover, COX-2 and HO-1 were significantly reduced only by the co-treatment, and melatonin aided EGCG to achieve an increased inhibition on Bcl2 and NFκB. These events occurring in the co-treatment collectively resulted in an enhanced cytotoxicity. In addition, the co-treatment also enhanced the inhibitory activities against cell migration and colony formation. Overall, the results gathered from these two cancer cell lines with a divergent p21 response to melatonin show that the various oncostatic activities of melatonin and EGCG together are more robust than each agent alone, suggesting that they may be useful partners in fighting cancer.
12
Song, Dongqiang, Beili Xu, Dongmin Shi, Shuyu Li, and Yu Cai. "S100A6 promotes proliferation and migration of HepG2 cells via increased ubiquitin-dependent degradation of p53." Open Medicine 15, no. 1 (April 20, 2020): 317–26. http://dx.doi.org/10.1515/med-2020-0101.
Full textAbstract:
AbstractPurposeS100A6 protein (calcyclin), a small calcium-binding protein of the S100 family, is often upregulated in various types of cancers, including hepatocellular carcinoma (HCC). The aim of this study was to illustrate the molecular mechanism of S100A6 in regulating the proliferation and migration of HCC cells.MethodsThe expressions of S100A6 in human HCC and adjacent non-tumor liver specimens were detected using immunoblotting and quantitative PCR (qPCR). The recombinant glutathione S-transferase (GST)-tagged human S100A6 protein was purified and identified. After treatment with S100A6, the proliferation of HepG2 cells was detected by the MTT and colony formation assay, and the migration of HepG2 cells was investigated by the transwell migration assay; the protein levels of cyclin D1 (CCND1), E-cadherin, and vimentin were also tested by immunoblotting. The effect of S100A6 on p21 and nuclear factor-κB pathway was verified by performing the dual luciferase assay. Then, the expression of p21 and its transcription activator, p53, was examined using immunoblotting and qPCR, the ubiquitination of which was investigated through co-immunoprecipitation.ResultsIt was found that the level of S100A6 was higher in the HCC tissues than in the adjacent non-tumor liver specimens. Exogenous overexpression of S100A6 promoted the proliferation and migration of HepG2 cells. S100A6 was observed to regulate p21 mRNA and protein expression levels and decrease p53 protein expression level, not mRNA level, by promoting the ubiquitination of p53 via the proteasome-dependent degradation pathway.ConclusionOur study indicated that S100A6 overexpression could promote the proliferation and migration of HCC cells by enhancing p53 ubiquitin-dependent proteasome degradation, ultimately regulating the p21 expression level.
13
Chen, Chiao-Ping, Chun-Nan Yeh, Yi-Ru Pan, Yu-Tien Hsiao, Chih-Hong Lo, Cai-Jhen Jhuang, and Chiao-En Wu. "Abstract 5289: Activating p53 through MDM2 and WIP1 inhibition effectively inhibits tumors in liver adenocarcinoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5289. http://dx.doi.org/10.1158/1538-7445.am2022-5289.
Full textAbstract:
Abstract Intrahepatic cholangiocarcinoma (iCCA) is an adenocarcinoma arising from the intrahepatic bile duct and accounts for the second most cases of primary liver cancers after hepatocellular carcinoma. Lacking effective treatment leads to a poor prognosis for advanced iCCA so new targeted therapy is warranted. Impaired wild-type (WT) p53 tumor suppressor function by its negative regulators frequently occurs in iCCA. Therefore, restoration of WT p53 function by inhibiting its negative regulators is a therapeutic strategy being explored for cancer treatment. Both MDM2 inhibitor (MDM2i, RG7388) stabilizing p53 and WIP1 inhibitor (WIP1i, GSK2830371) increasing p53 phosphorylation lead to maximize p53 function. The combination of MDM2i/WIP1i has been reported in severe cancer types but no in vivo study has been done. In the current study, both liver adenocarcinoma cell lines, RBE and SK-Hep-1, were treated with the RG7388 alone and in combination with GSK2830371. Cell proliferation, clonogenicity, protein and mRNA expressions, and cell cycle distribution were performed to investigate the effect and mechanism of growth suppression. To evaluate the antitumor efficacy of RG7388 and GSK2830371 in vivo, xenografts with SK-Hep-1 cells were treated with combination therapy for two weeks in NOD-SCID mice. The combination of MDM2i and WIP1i significantly increased the growth inhibition, cytotoxic activity, increased p53 protein expression, and phosphorylation (Ser 15), leading to transactivation of downstream targets (p21 and MDM2). The in vivo test demonstrated that the combination treatment can significantly inhibit tumor growth. In this study, liver adenocarcinoma cell lines were inhibited by the combination via reactivation of p53 function evidenced by increased p53 expression, phosphorylation and its downstream targets. This efficacy was also validated by in vivo study. The current research provides a novel strategy for targeting the p53 pathway in liver adenocarcinoma. Citation Format: Chiao-Ping Chen, Chun-Nan Yeh, Yi-Ru Pan, Yu-Tien Hsiao, Chih-Hong Lo, Cai-Jhen Jhuang, Chiao-En Wu. Activating p53 through MDM2 and WIP1 inhibition effectively inhibits tumors in liver adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5289.
14
Sheel, Ankur, SuetYan Kwan, and Wen Xue. "Integrating CRISPR screening with tumor genomic analyses to identify therapeutic targets in hepatocellular carcinomas (HCC) independent of P53." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14659-e14659. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14659.
Full textAbstract:
e14659 Background: Hepatocellular carcinoma (HCC) is an aggressive subtype of liver cancer with few effective treatments. Moreover, the underlying mechanisms that drive HCC pathogenesis remain poorly characterized. Identifying genes and pathways essential for HCC cell growth will aid the development of new targeted therapies for HCC. Furthermore, the P53 pathway is frequently mutated in HCC therefore identifying targets with therapeutic efficacy irrespective of P53 status is warranted. Methods: To identify kinases essential for HCC proliferation, we performed a kinome wide CRISPR screen in human HCC cell lines with varying P53 mutations and validated our findings using CRISPR-Cas9 mediated genetic manipulations in human HCC cell lines in-vitro and in-vivo. Furthermore, we performed an integrated cancer genomics analyses using patient data from TCGA and the NCI to validate the relevancy of our findings. Results: We identified transformation/transcription domain-associated protein (TRRAP) as an essential gene for HCC cell proliferation. we show that depletion of TRRAP or its co-factor, histone acetyltransferase KAT5, inhibits HCC cell growth via induction of P53, P21 and RB-independent senescence in-vitro and in-vivo. Furthermore, we find that TRRAP is upregulated in HCC patient samples independent of TP53 mutations. Integrated cancer genomics analyses using both HCC patient data derived from TCGA and from RNA-sequencing of our in-vitro model identified a chromosomal instability signature that was regulated by TRRAP/KAT5 in-vitro. Furthermore this chromosomal instability signature was also upregulated in HCC patients. Finally, we identify TOP2A as a target in this pathway as genetic depletion of TOP2A inhibited cell growth via induction of senescence. Conclusions: Our results uncover a role for TRRAP/KAT5 in promoting HCC cell proliferation via activation of mitotic genes in order to potentiate a chromosomal instability signature. Our findings suggest that targeting the TRRAP/KAT5 complex and TOP2A is a therapeutic strategy for HCC, even in tumors that have escaped P53 and RB tumor suppressive programs.
15
Chen, Zhiqiang, Xueliang Zuo, Liyong Pu, Yao Zhang, Guoyong Han, Long Zhang, Jindao Wu, and Xuehao Wang. "circ LARP 4 induces cellular senescence through regulating miR‐761/ RUNX 3/p53/p21 signaling in hepatocellular carcinoma." Cancer Science 110, no. 2 (January 4, 2019): 568–81. http://dx.doi.org/10.1111/cas.13901.
Full text
16
Chang, Kai-Fu, Xiao-Fan Huang, Yu-Ling Lin, Kuang-Wen Liao, Ming-Chang Hsieh, Jinghua Tsai Chang, and Nu-Man Tsai. "Positively Charged Nanoparticle Delivery of n-Butylidenephthalide Enhances Antitumor Effect in Hepatocellular Carcinoma." BioMed Research International 2021 (March 19, 2021): 1–14. http://dx.doi.org/10.1155/2021/8817875.
Full textAbstract:
Hepatocellular carcinoma (HCC) is the second and sixth leading cause of cancer death in men and woman in 185 countries statistics, respectively. n-Butylidenephthalide (BP) has shown anti-HCC activity, but it also has an unstable structure that decreases its potential antitumor activity. The aim of this study was to investigate the cell uptake, activity protection, and antitumor mechanism of BP encapsulated in the novel liposome LPPC in HCC cells. BP/LPPC exhibited higher cell uptake and cytotoxicity than BP alone, and combined with clinical drug etoposide (VP-16), BP/LPPC showed a synergistic effect against HCC cells. Additionally, BP/LPPC increased cell cycle regulators (p53, p-p53, and p21) and decreased cell cycle-related proteins (Rb, p-Rb, CDK4, and cyclin D1), leading to cell cycle arrest at the G0/G1 phase in HCC cells. BP/LPPC induced cell apoptosis through activation of both the extrinsic (Fas-L and Caspase-8) and intrinsic (Bax and Caspase-9) apoptosis pathways and activated the caspase cascade to trigger HCC cell death. In conclusion, the LPPC complex improved the antitumor activity of BP in terms of cytotoxicity, cell cycle regulation and cell apoptosis, and BP/LPPC synergistically inhibited cell growth during combination treatment with VP-16 in HCC cells. Therefore, BP/LPPC is potentially a good candidate for clinical drug development or for use as an adjuvant for clinical drugs as a combination therapy for hepatocellular carcinoma.
17
OU, XIANHONG, YOU LU, LIUFENG LIAO, DANNI LI, LIMIN LIU, HUAGANG LIU, and HENG XU. "Nitidine chloride induces apoptosis in human hepatocellular carcinoma cells through a pathway involving p53, p21, Bax and Bcl-2." Oncology Reports 33, no. 3 (December 22, 2014): 1264–74. http://dx.doi.org/10.3892/or.2014.3688.
Full text
18
Zhu, Hanzhang, Jingrui Wang, Junjie Yin, Bei Lu, Qijun Yang, Yafeng Wan, and Changku Jia. "Downregulation of PRAME Suppresses Proliferation and Promotes Apoptosis in Hepatocellular Carcinoma Through the Activation of P53 Mediated Pathway." Cellular Physiology and Biochemistry 45, no. 3 (2018): 1121–35. http://dx.doi.org/10.1159/000487353.
Full textAbstract:
Background/Aims: The expression of PRAME and its role in hepatocellular carcinoma (HCC) remain unknown. The aim of this study was to examine the functional role of PRAME in HCC development and exploring the molecular mechanism. Methods: We first detected PRAME expression in 96 human HCC tissue samples and correlated with clinicopathological characteristics and prognosis of the patients. We then established stable HCC cell lines with PRAME overexpression and knockdown followed by functional analysis in vitro. Further, we examined the relationship between PRAME and p53 pathway in vitro by using Western blotting. Finally, PRAME expression was detected to evaluate its correlation with p-p53 and p53 pathway related apoptotic proteins in xenograft tumor mouse model using immunohistochemistry. Results: PRAME expression was significantly higher in HCC tissues than in adjacent non-tumor tissues and their expression was positively correlated with alpha fetoprotein levels and tumor size. In addition, PRAME expression was associated with AJCC stage and is a potential biomarker of poor prognosis regarding 5-year overall survival in HCC. In vitro studies, we found that PRAME expression was higher in HCC cell lines than in normal hepatic cell line. Inhibited cell proliferation and increased cell apoptosis was observed in PRAME knockdown HCC cells. Futher, increased cell apoptosis was correlated with the proportion of cells in G0/G1 stage, activated p53 mediated apoptosis, and increased cyclin p21 expression. Xenograft analysis in nude mice also found that PRAME knockdown inhibited tumorigenesis while PRAME overexpression had opposite effect. Conclusions: In HCC, PRAME serves as a potential biomarker for poor prognosis and novel therapeutic target in treating this cancer. PRAME is a potential biomarker of poor prognosis in HCC. PRAME surpresses HCC cell death in vitro and in vivo by regulating p53 apoptotic signaling and may serve as a potential therapeutic target in HCC.
19
Wang, Qingqing, Xiaoyan Yu, Zhewen Zheng, Fengxia Chen, Ningning Yang, and Yunfeng Zhou. "Centromere protein N may be a novel malignant prognostic biomarker for hepatocellular carcinoma." PeerJ 9 (May 3, 2021): e11342. http://dx.doi.org/10.7717/peerj.11342.
Full textAbstract:
Background Hepatocellular carcinoma (HCC) is one of the deadliest tumors. The majority of HCC is detected in the late stage, and the clinical results for HCC patients are poor. There is an urgent need to discover early diagnostic biomarkers and potential therapeutic targets for HCC. Methods The GSE87630 and GSE112790 datasets from the Gene Expression Omnibus (GEO) database were downloaded to analyze the differentially expressed genes (DEGs) between HCC and normal tissues. R packages were used for Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses of the DEGs. A Search Tool for Retrieval of Interacting Genes (STRING) database was used to develop a protein-protein interaction (PPI) network, and also cytoHubba, Molecular Complex Detection (MCODE), EMBL-EBI, CCLE, Gene Expression Profiling Interactive Analysis (GEPIA), and Oncomine analyses were performed to identify hub genes. Gene expression was verified with a third GEO dataset, GSE25097. The Cancer Genome Atlas (TCGA) database was used to explore the correlations between the hub genes and clinical indexes of HCC patients. The functions of the hub genes were enriched by gene set enrichment analysis (GSEA), and the biological significance of the hub genes was explored by real-time polymerase chain reaction (qRT-PCR), western blot, immunofluorescence, CCK-8, colony formation, Transwell and flow cytometry assays with loss-of-function experiments in vitro. Results Centromere protein N (CENPN) was screened as a hub gene affecting HCC tumorigenesis. Evaluation by Cox regression showed that a high level of CENPN expression was an independent danger variable for poor prognosis of HCC. GSEA showed that high CENPN expression was linked to the following pathways: liver cancer subclass proliferation, cell cycle, p53 signaling pathway, Rb1 pathway, positive regulation of cell cycle G1/S phase transition, and DNA damage response signal transduction by p53 class moderators. Further cell experiments showed that knocking down CENPN expression decreased the proliferation and colony-forming abilities of HepG2 and Huh7 cells as well as Ki67 expression in these cell lines. The cell cycle was arrested in G1 phase, which is consistent with previous experiments on CENPN downregulation., but neither migration nor invasion were significantly affected. Western blot results revealed that the expression of p53, p27, p21, CDK4, cyclin D1, CDK2, cyclin E, pRb, E2F1 and c-myc decreased after CENPN knockdown, but there was no significant change in total Rb levels. In addition, CENPN-knockdown cells subjected to irradiation showed significantly enhanced of γ-H2AX expression and reduced colony formation. Conclusion CENPN functions as an oncogene in HCC and may be a therapeutic target and promising prognostic marker for HCC.
20
Wang, Jiahui, Xin Liu, Hongjin Chu, and Jian Chen. "Cell division cycle associated 2 (CDCA2) upregulation promotes the progression of hepatocellular carcinoma in a p53-dependant manner." PeerJ 10 (June 6, 2022): e13535. http://dx.doi.org/10.7717/peerj.13535.
Full textAbstract:
Background Elevated expression and oncogenic functions of cell division cycle associated 2 (CDCA2), an important mitotic regulator, have been demonstrated in several cancer types, however their involvement in hepatocellular carcinoma (HCC) has not been elucidated, and the underlying molecular mechanism remains unclear. This study aims to determine the role of CDCA2 in HCC and the underlying molecular mechanism. Methods The expression of CDCA2 in HCC was studied in 40 pairs of frozen and 48 pairs of paraffin-embedded HCC samples and paracancerous normal samples by qRT-PCR and immunohistochemistry, respectively, and using The Cancer Genome Atlas (TCGA) datasets. The cellular function of CDCA2 was studied in vitro in the HepG2, Huh7 and SK-Hep1 HCC cell lines. Results We found significantly upregulated CDCA2 expression in HCC, which was correlated with higher clinical stage, tumor grade and Glypican-3 (+). High CDCA2 expression was correlated with worse overall survival. CDCA2 promoted the proliferation of HCC cells by promoting G1/S transition through the upregulation and activation of CCND1/CDK4/6 and CCNE1/CDK2, enhanced the clonogenic ability, inhibited apoptosis in a p53/p21-dependent manner by inhibiting the p38 MAPK pathway and activating the JNK/c-Jun pathway, and promoted the migration of p53-mutant Huh7 cells by activating the epithelial-mesenchymal transition. Targeting CDCA2 reduced the chemoresistance of HCC cells to cisplatin. CDCA2 expression was also regulated by cyclophilin J. Conclusions This study revealed elevated expression of CDCA2 in HCC, possibly as a result of p53 dysregulation, which was associated with worse prognosis of patients. We confirmed the oncogenic role of CDCA2 in HCC in vitro and revealed some of the underlying molecular mechanisms. This study indicated the potential value of CDCA2 as a future target for the treatment of HCC.
21
Wang, Wenping, Yi Liu, Mingyi Sun, Na Sai, Longtai You, Xiaoxv Dong, Xingbin Yin, and Jian Ni. "Hepatocellular Toxicity of Paris Saponins I, II, VI and VII on Two Kinds of Hepatocytes-HL-7702 and HepaRG Cells, and the Underlying Mechanisms." Cells 8, no. 7 (July 9, 2019): 690. http://dx.doi.org/10.3390/cells8070690.
Full textAbstract:
Rhizoma paridis is a popularly-used Chinese medicine in clinics, based on the pharmacodynamic properties of its saponin components. The four main saponins in Rhizoma paridis are designated saponins I, II, VI, and VII. At present, much attention is focused on the anticancer effect of Rhizoma paridis which is manifested in its cytotoxicity to various cancer cells. The purpose of this study was to investigate the hepatocellular toxicities of the four saponins in Rhizoma paridis and the relative intensities of their cytotoxic effects. It was found that the four saponins were cytotoxic to two types of hepatocytes-HL-7702 and HepaRG cells. The cytotoxicities of the four saponins to the two cell models were compared. One of the most cytotoxic saponins was Rhizoma paridis saponin I (PSI). This was used to determine the mechanism of hepatocellular toxicity. Results from MTT assays demonstrated that the four saponins induced apoptosis of the two hepatocyte models in a dose-dependent and time-dependent manner. In addition, fluorescent 4′,6-diamidino-2-phenylindole (DAPI) staining was used to observe the morphological changes of HepaRG cells after saponin administration. Further, as the concentration increased, PSI-induced lactate dehydrogenase (LDH) release from HepaRG cells increased gradually. In addition, PSI enhanced the levels of reactive oxygen species (ROS) and blocked the S and G2 phases of the cell cycle in HepaRG cells. A western blot indicated that PSI upregulated the protein expression levels of p53, p21, and Fas. Furthermore, the PSI-induced changes in the p53 protein increased the Bax/bcl-2 ratio, resulting in enhancement of the release of mitochondrial cytochrome c, activation of caspases-3, -8, and -9, poly-ADP ribose polymerase (PARP), and ultimately apoptosis. Increased Fas protein activated caspase-8, which led to the activation of caspase-3 and its downstream PARP protein, resulting in cell apoptosis. These results indicate that PSI induced apoptosis in HepaRG cells through activation of ROS and death receptor pathways. The results obtained in this study suggest that the hepatocellular toxicity of saponins in Rhizoma paridis should be considered during the clinical application of this drug. In addition, they provide a reference for future anti-cancer studies on Rhizoma paridis.
22
Jannus, Fatin, Marta Medina-O’Donnell, Francisco Rivas, Luis Díaz-Ruiz, Eva E. Rufino-Palomares, José A. Lupiáñez, Andrés Parra, and Fernando J. Reyes-Zurita. "A Diamine-PEGylated Oleanolic Acid Derivative Induced Efficient Apoptosis through a Death Receptor and Mitochondrial Apoptotic Pathway in HepG2 Human Hepatoma Cells." Biomolecules 10, no. 10 (September 28, 2020): 1375. http://dx.doi.org/10.3390/biom10101375.
Full textAbstract:
Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Our recent studies have shown that the diamine-(PEG)ylated oleanolic acid (OADP) has strong anti-tumor effects in HCCs. In this study, we evaluated the anti-tumor mechanisms of OADP in the HepG2 HCC cell line. The cytotoxicity results showed that HepG2 cell viability was markedly reduced, with a very low 50% of cell growth inhibitory concentration (IC50, 0.14 µg/mL). We then investigated the anti-tumor mechanisms of OADP in HepG2 cells. The flow-cytometry analysis was used to evaluate cell apoptosis, indicating that 74–95% of cells were apoptotic. OADP caused cell cycle arrest in the G0/G1 phase and the loss of the mitochondrial membrane potential (MMP). Western blot analysis was performed to assess the expression levels of key proteins associated with the underlying molecular mechanism. The results showed the clear upregulation of caspase-8, caspase-9, caspase-3, Bak, p21, and p53, accompanied by the downregulation of Bcl-2. Similar results were obtained by the cotreatment with OADP and the c-Jun N-terminal kinase (JNK) inhibitor SP600125. Agents such as OADP, which are capable of activating extrinsic and intrinsic apoptotic pathways, may represent potential HCC cancer therapies.
23
Kim, Yu Jin, Nayeong Yuk, Hee Jeong Shin, and Hye Jin Jung. "The Natural Pigment Violacein Potentially Suppresses the Proliferation and Stemness of Hepatocellular Carcinoma Cells In Vitro." International Journal of Molecular Sciences 22, no. 19 (October 3, 2021): 10731. http://dx.doi.org/10.3390/ijms221910731.
Full textAbstract:
Hepatocellular carcinoma (HCC) is a malignant type of primary liver cancer with high incidence and mortality, worldwide. A major challenge in the treatment of HCC is chemotherapeutic resistance. It is therefore necessary to develop novel anticancer drugs for suppressing the growth of HCC cells and overcoming drug resistance for improving the treatment of HCC. Violacein is a deep violet-colored indole derivative that is produced by several bacterial strains, including Chromobacterium violaceum, and it possesses numerous pharmacological properties, including antitumor activity. However, the therapeutic effects of violacein and the mechanism underlying its antitumor effect against HCC remain to be elucidated. This study is the first to demonstrate that violacein inhibits the proliferation and stemness of Huh7 and Hep3B HCC cells. The antiproliferative effect of violacein was attributed to cell cycle arrest at the sub-G1 phase and the induction of apoptotic cell death. Violacein induced nuclear condensation, dissipated mitochondrial membrane potential (MMP), increased generation of reactive oxygen species (ROS), activated the caspase cascade, and upregulated p53 and p21. The anticancer effect of violacein on HCC cells was also associated with the downregulation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK)1/2 signaling. Violacein not only suppressed the proliferation and formation of tumorspheres of Huh7 and Hep3B cancer stem-like cells but also reduced the expression of key markers of cancer stemness, including CD133, Sox2, Oct4, and Nanog, by inhibiting the signal transducer and activator of transcription 3 (STAT3)/AKT/ERK pathways. These results suggest the therapeutic potential of violacein in effectively suppressing HCC by targeting the proliferation and stemness of HCC cells.
24
Gee, Min Sung, Sung-Bae Kang, Namkwon Kim, Jiyoon Choi, Nam-Jung Kim, Bum-Joon Kim, Kyung-Soo Inn, and Jong Kil Lee. "Bardoxolone Methyl Suppresses Hepatitis B Virus Large Surface Protein Variant W4P-Related Carcinogenesis and Hepatocellular Carcinoma Cell Proliferation Via the Inhibition of Signal Transducer and Activator of Transcription 3 Signaling." Pharmacology 102, no. 1-2 (2018): 105–13. http://dx.doi.org/10.1159/000489998.
Full textAbstract:
Bardoxolone methyl (CDDO-me) is a synthetic triterpenoid that has been shown to suppress various cancers and inflammation. It has been implicated for the suppression of signal transducer and activator of transcription 3 (STAT3)-mediated signaling, which plays crucial roles in the development and progression of hepatocellular carcinoma (HCC). Previously, we showed that hepatitis B virus (HBV) large surface protein (LHB) variant W4P promotes carcinogenesis and tumor progression through STAT3 activation. Thus, we examined the anti-cancer activity of CDDO-me against HCC using W4P-LHB-expressing NIH3T3 cells and HepG2 and Huh7 HCC cell lines. CDDO-me exerted cytotoxic activity against W4P-LHB-expressing NIH3T3 cells, HepG2 cells, and Huh7 cells, and induced apoptotic cell death in a dose-dependent manner, demonstrating its anti-cancer activity against HCC. Sublethal concentrations of CDDO-me suppressed STAT3 activation by W4P-LHB ectopic expression and interleukin-6 treatment in W4P-LHB-NIH3T3 and Huh7 cells respectively. The suppression of STAT3 activation by CDDO-me in W4P-LHB-NIH3T3 cells was further confirmed by decreased cyclin D1 protein levels and increased p21 and p53 mRNA synthesis. In addition, CDDO-me treatment resulted in decreased cell migration and colony formation in in vitro assays using W4P-LHB-NIH3T3, HepG2, or Huh7 cell lines, supporting its anti-cancer activity through STAT3 inhibition. Furthermore, CDDO-me administration significantly suppressed tumor growth induced by W4P-LHB-expressing NIH3T3 cells in nude mice, confirming its anti-cancer activity. Collectively, our findings demonstrated that CDDO-me is capable of suppressing STAT3 activation in HCC cells and cells transformed by the natural variant of HBV protein. The results suggest that CDDO-me can be a potential therapeutic agent against HCC, especially tumors related to HBV mutations.
25
Fyala, A. S., and A. S. Sultan. "Co-treatment of Garlic-Oils Extract, Dially-thiosulphate, and Histone Deacetylases Inhibitors (HDACI) Synergistically Inhibited Cell Proliferation and induced Apoptosis in Hepatocellular carcinoma cell lines." American Journal of Clinical Pathology 156, Supplement_1 (October 1, 2021): S137. http://dx.doi.org/10.1093/ajcp/aqab191.292.
Full textAbstract:
Abstract Introduction/Objective Hepatocellular carcinoma (HCC) is the most common cause of cancer-deaths worldwide. Garlic (Allium Sativum), is a natural-medicinal herb which has anti-fungal, anti-bacterial, anti-inflammatory, anti-virus, and antiproliferative activities. Garlic-oil soluble-sulfur-compounds, diallyl-thiosulphate, (DT) are more effective than water-soluble-compounds in protection against cancer due to its capacity to induce apoptosis and revise anti- multidrug-resistance. Histone deacetylases inhibitors (HDACIs) are inhibitors of anti-cancer agents that play a role in inducing death, differentiation, apoptosis induction, and cell-cycle arrest in different cancer-types. The present studying aims to investigate the anti-proliferative effect of organosulfur-oil DT extract of garlic by possible modulation of HDACIs role on HCC cell-lines. Methods/Case Report Two HDACIs, suberanilohydroxamic acid (SAHA) and trichostatinA (TSA), were used to investigate their role on proliferation of two HCC cell-lines, HepG2 and Hep3B, respectively. Cell proliferation was examined by Wst-1 assay, apoptosis induction signaling pathways, cell-cycle analysis, and western-blot analysis of the major oncogenic signaling pathways in the two tested cell-lines. Results (if a Case Study enter NA) Our data showed that DT significantly inhibited the cell-proliferation and induced cell-cycle arrest at G2/M phase in both HCC cell-lines. In addition, co-treatment of DT and HDACIs for 48h enhanced the cell inhibitory effect and induced apoptosis by up-regulation of p53, p21, and Bax protein expression and down- regulation of Bcl-2 and cyclin-D1 protein expression compared to control or each treatment alone. Furthermore, the data showed that DT significantly increased caspases-3 activity in Hep-G2 cell-line than that of Hep3B cell-line in a dose dependent-time compared to the control. Apoptosis induction was consistent with up-regulated caspase-3 activity, and HepG2 cells, but not Hep3B cells, showed a significant increase in response to co-treatment of DT with SAHA compared to co-treatment with TSA. Conclusion The data of the present study demonstrated that DT, non-toxicity compound, might be a new modulator for HDACIs effects, which in turn might be a promising prospective agent for HCC treatment.
26
Liu, Kaikun, Yumin Li, Bo Yu, Furong Wang, Taiyu Mi, and Yongxun Zhao. "Silencing non-SMC chromosome-associated polypeptide G inhibits proliferation and induces apoptosis in hepatocellular carcinoma cells." Canadian Journal of Physiology and Pharmacology 96, no. 12 (December 2018): 1246–54. http://dx.doi.org/10.1139/cjpp-2018-0195.
Full textAbstract:
The present study was designed to investigate the significance of non–structural maintenance of chromosomes (non-SMC) chromosome-associated polypeptide G (NCAPG), a subunit of condensin complex I, in the development of hepatocellular carcinoma (HCC). NCAPG protein expression in human HCC and paracancerous hepatic tissues were examined using immunohistochemistry, and NCAPG mRNA expression in HCC cell lines were quantified using quantitative RT–PCR. Lentivirus-mediated RNA interference was used to silence NCAPG in HCC cells. Cell proliferation was monitored by MTT assay. Cell colony-forming capacity was measured by colony formation assay. Apoptosis was determined by flow cytometry. The results showed that increased protein expression of NCAPG was found in HCC tissues compared with the matched paracancerous hepatic tissues. At the mRNA level, increased expression of NCAPG was found in HCC cells as opposed to the normal hepatocytes. Silencing of NCAPG in BEL-7404 and SMMC-7721 cells led to decreased cell proliferation and increased apoptosis. These changes were associated with increased mRNA expressions of P53, P27, and Bad, but decreased mRNA expression of EGFR, Akt, survivin, and JNK. NCAPG might play an oncogenic role in the development of liver cancer. Further studies to clarify its role and underlying mechanisms in the development of liver cancer are warranted.
27
Shariat, Shahrokh F., Hideo Tokunaga, JainHua Zhou, JaHong Kim, Gustavo E. Ayala, William F. Benedict, and Seth P. Lerner. "p53, p21, pRB, and p16 Expression Predict Clinical Outcome in Cystectomy With Bladder Cancer." Journal of Clinical Oncology 22, no. 6 (March 15, 2004): 1014–24. http://dx.doi.org/10.1200/jco.2004.03.118.
Full textAbstract:
Purpose To determine whether p53, p21, pRB, and/or p16 expression is associated with bladder cancer stage, progression, and prognosis. Patients and Methods Immunohistochemical staining for p53, p21, pRB, and p16 was carried out on serial sections from archival specimens of 80 patients who underwent bilateral pelvic lymphadenectomy and radical cystectomy for bladder cancer (median follow-up, 101 months). Results p53, p21, and pRB or p16 expression was altered in 45 (56%), 39 (49%), and 43 (54%) tumors, respectively. Sixty-six patients (83%) had at least one marker altered, and 21 patients (26%) had all three altered. Abnormal expressions of p53, p21, and pRB/p16 expression were associated with muscle-invasive disease (P = .007, P = .003, and P = .003, respectively). The alteration of each marker was independently associated with disease progression (P ≤ .038) and disease-specific survival (P ≤ .039). In multivariable models that included standard pathologic features and p53 with p21 or p53 with pRB/p16, only p53 and lymph node metastases were associated with bladder cancer progression (P ≤ .026) and death (P ≤ .028). In models that included p21 and pRB/p16, only p21 and lymph node metastases were associated with bladder cancer progression (P ≤ .022) and death (P ≤ .028). In a model that included the combined variables p53/p21 and pRB/p16, only p53/p21 and lymph node status were associated with bladder cancer progression (P ≤ .047) and death (P ≤ .036). The incremental number of altered markers was independently associated with an increased risk of bladder cancer progression (P = .005) and mortality (P = .007). Conclusion Although altered expression of each of the four cell cycle regulators is associated with bladder cancer outcome in patients undergoing radical cystectomy, p53 is the strongest predictor, followed by p21, suggesting a more pivotal role of the p53/p21 pathway in bladder cancer progression.
28
Shoji, Tsuyoshi, Fumihiro Tanaka, Tetsuya Takata, Kazuhiro Yanagihara, Yosuke Otake, Nobuharu Hanaoka, Ryo Miyahara, et al. "Clinical Significance of p21 Expression in Non–Small-Cell Lung Cancer." Journal of Clinical Oncology 20, no. 18 (September 15, 2002): 3865–71. http://dx.doi.org/10.1200/jco.2002.09.147.
Full textAbstract:
PURPOSE: The clinical significance of p21 expression remains unclear, whereas many experimental studies have demonstrated that p21, the product of the WAF1/CIP1/SDI1 gene, plays an important role in regulation of the cell cycle as an inhibitor of cyclin-dependent kinases. The purpose of this study was to clarify the clinical significance in resected non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 233 consecutive patients with completely resected pathologic stage I to IIIA NSCLC were retrospectively reviewed. Expression of p21 and the status of p53 were examined immunohistochemically. Proliferative activity was also evaluated immunohistochemically. The incidence of apoptotic cell death was evaluated by terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate-biotin nick end-labeling staining. RESULTS: Expression of p21 was positive in 120 patients (51.5%). The 5-year survival rate of p21-positive patients was 73.8%, significantly higher than that of p21-negative patients (60.7%; P = .006). Aberrant expression of p53 was positive in 98 patients (42.1%). When combined with p53 status, the prognostic value of p21 status was enhanced: the 5-year survival rate of p21-positive and p53-negative patients was 80.7%, markedly higher than that of p21-negative and p53-positive patients (50.0% for both; P = .001). Multivariate analysis confirmed that positive expression of p21 was a significant factor for predicting a favorable prognosis. There was no significant correlation between p21 expression and p53 status, proliferative activity, or incidence of apoptosis. CONCLUSION: p21 expression was shown to be an independent prognostic factor in NSCLC.
29
Shamloo and Usluer. "p21 in Cancer Research." Cancers 11, no. 8 (August 14, 2019): 1178. http://dx.doi.org/10.3390/cancers11081178.
Full textAbstract:
p21 functions as a cell cycle inhibitor and anti-proliferative effector in normal cells, and is dysregulated in some cancers. Earlier observations on p21 knockout models emphasized the role of this protein in cell cycle arrest under the p53 transcription factor activity. Although tumor-suppressor function of p21 is the most studied aspect of this protein in cancer, the role of p21 in phenotypic plasticity and its oncogenic/anti-apoptotic function, depending on p21 subcellular localization and p53 status, have been under scrutiny recently. Basic science and translational studies use precision gene editing to manipulate p21 itself, and proteins that interact with it; these studies have led to regulatory/functional/drug sensitivity discoveries as well as therapeutic approaches in cancer field. In this review, we will focus on targeting p21 in cancer research and its potential in providing novel therapies.
30
Aurora, V., S. Li, S. J. Horning, D. Variakojis, B. P. Nelson, M. Krajewska, T. M. Habermann, R. I. Fisher, R. D. Gascoyne, and J. N. Winter. "Prognostic significance of p53/p21 expression in DLBCL treated with CHOP or R-CHOP: A correlative study of E4494." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 8038. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.8038.
Full textAbstract:
8038 Background: P21 is a downstream effector protein of p53 that induces cell cycle arrest by inhibiting cyclin/cyclin dependent kinase (cdK) complexes. In this prospective correlative study, we investigated the prognostic significance of p21, p53, Bcl-6, and Bcl-2 in diffuse large B cell lymphoma (DLBCL) in the context of E4494, a randomized trial comparing conventional CHOP to rituximab(R)-CHOP induction, and maintenance R (MR) to observation for responding patients. Methods: Protein expression was quantified by immunohistochemical (IHC) staining of 198 DLBCL paraffin-embedded biopsy specimens and scored by an expert panel of hematopathologists. Results: No differences in the distribution of patient characteristics were detected between p21+ and p21- cases and between p53+ and p53- cases as well as across treatment arms. Among all study patients, there were no differences in clinical outcomes between p21+ and p21- cases. However, when analyzed by induction arm (removing the effect of MR), R-CHOP patients had marginally better FFS (p=0.06) if p21+; among CHOP-treated patients, p21 status had no effect on outcome. For R-CHOP patients but NOT CHOP patients, p21+ was an independent, favorable prognostic factor after adjusting for Bcl-6, IPI and Bcl-2 in multivariate analysis (FFS relative risk 0.3; p=0.003; OS relative risk 0.4; p=0.02). P21+ patients treated with R-CHOP had higher %FFS at 5 years compared to p21+ patients treated with CHOP (61 ± 7% vs. 24 ± 7%; p=0.007) but p21- R-CHOP and CHOP patients had similar FFS (37 ± 7% vs. 35 ± 7%; p=0.64). P53 staining (+ scored as either >20% or 50%) did not predict for FFS or OS in uni- or multivariate analyses. The p53+/p21- phenotype, a possible surrogate for mutated p53, was not prognostic. Further, no significant correlation was seen between p53 and p21 expression by IHC. Conclusions: These data suggest that p21 expression by IHC predicts for favorable outcome in older DLBCL patients treated with R-CHOP but not in those treated with CHOP. Furthermore, p21+ identifies patients who benefit from the addition of rituximab to CHOP. Complex interactions between p53, p21, and Bcl-6, as well as other unknown pathways, may account for this treatment-related effect and should be further investigated. [Table: see text]
31
Mirzayans, Razmik, Bonnie Andrais, April Scott, and David Murray. "New Insights into p53 Signaling and Cancer Cell Response to DNA Damage: Implications for Cancer Therapy." Journal of Biomedicine and Biotechnology 2012 (2012): 1–16. http://dx.doi.org/10.1155/2012/170325.
Full textAbstract:
Activation of the p53 signaling pathway by DNA-damaging agents was originally proposed to result either in cell cycle checkpoint activation to promote survival or in apoptotic cell death. This model provided the impetus for numerous studies focusing on the development of p53-based cancer therapies. According to recent evidence, however, most p53 wild-type human cell types respond to ionizing radiation by undergoing stress-induced premature senescence (SIPS) and not apoptosis. SIPS is a sustained growth-arrested state in which cells remain viable and secrete factors that may promote cancer growth and progression. Thep21WAF1(hereafter p21) protein has emerged as a key player in the p53 pathway. In addition to its well-studied role in cell cycle checkpoints, p21 regulates p53 and its upstream kinase (ATM), controls gene expression, suppresses apoptosis, and induces SIPS. Herein, we review these and related findings with human solid tumor-derived cell lines, report new data demonstrating dynamic behaviors of p53 and p21 in the DNA damage response, and examine the gain-of-function properties of cancer-associated p53 mutations. We point out obstacles in cancer-therapeutic strategies that are aimed at reactivating the wild-type p53 function and highlight some alternative approaches that target the apoptotic threshold in cancer cells with differing p53 status.
32
Geisler, Hans E., John P. Geisler, Greg A. Miller, Marcia J. Geisler, Michael C. Wiemann, Zhen Zhou, and William Crabtree. "p21 and p53 in ovarian carcinoma." Cancer 92, no. 4 (2001): 781–86. http://dx.doi.org/10.1002/1097-0142(20010815)92:4<781::aid-cncr1383>3.0.co;2-p.
Full text
33
Woo, Jacky, Weiguo Wu, Vladislava O. Melnikova, Kenna Lynn Anderes, and Darren W. Davis. "Development of a quantitative immunofluorescent method for analysis of nuclear and cytoplasmic p53 and p21 in circulating tumor cells (CTC) as biomarkers of response to p53-targeted therapy." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e13575-e13575. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e13575.
Full textAbstract:
e13575 Background: The tumor suppressor p53 is involved in many aspects of cell cycle control and p53 mutations are the most common genetic abnormality in solid tumors. Several diverse approaches targeting p53 signaling including activators of p53, cell cycle checkpoint inhibitors and MdM2 inhibitors are under development and will require determination of p53 status to demonstrate proof of concept and ultimately drive patient selection. Measurement of p53 status in tumor biopsies is often hindered by limited availability of tissues. Detection of p53 status in CTCs offers an alternative to biopsy. Methods: A multiplex immunofluorescent (IF) method for identification of CTCs was developed using cytokeratin, CD45 and DAPI. DO7, a p53 specific antibody, and total and phospho-p21 antibodies were optimized for multiplex detection. Bleomycin (50 mU/mL) was used to activate p53 in A549 p53 wt cells, HT29 and SkBr3 p53 mutant cells. Single cell-based IF analysis was performed pre and post treatment by quantitative Laser Scanning Cytometry (LSC). Results: Wild type A549 cells expressed lower baseline levels of nuclear p53 compared to mutant p53 cell lines HT29 and SKBr3. Total and phosphorylated p21 was also lower in A549 cells compared to HT29 and SKBr3 cells. Bleomycin treatment of wt A549 cells led to a transient increase in p53 expression by 30% while mutant HT29 and SKBr3 cells did not show any change in p53. Treatment of A549 cells with bleomycin led to a 100% increase in total p21and a 70% increase in phosphorylated p21. No change in p21 was observed in p53 mutant HT29 and SKBr3 cell lines. Conclusions: We developed a sensitive, quantitative method for detection of nuclear and cytoplasmic p53 and p21 protein in cell lines that functionally discriminates between p53 wt and p53 mutant status. The method is transferable to circulating tumor cells (CTCs) and may have utility in selecting patients based on functional p53 status and predicting responses to p53 pathway targeted agents.
34
Li, Xiaofan, Shao Wen, and Shanwen Zhang. "Effect of p53 gene transfection on proliferation, apoptosis, and radiosensitivity of cervical cancer cells." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e22024-e22024. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e22024.
Full textAbstract:
e22024 Background: To investigate the effects of p53 gene transfection on proliferation, apoptosis and radio-sensitivity of cervical cancer cells. Methods: Two cervical cell lines: Siha with wild-type p53 gene and C33a with mutant p53 gene, were transfected with human wild-type p53 gene. Un-transfected cells and transfected cells were exposed to 6 Gy of radiation. Cell proliferation, apoptosis, and protein expressions of p53, MDM2, p21, and bax in the un-treated, p53- transfected, and irradiated cells were analyzed. Results: The protein expression of p53, MDM2, p21, and bax in the untreated Siha cells is very low; High level p53 and MDM2 proteins and low level of p21 and bax proteins were found in the untreated C33a cells. When transfected with recombinant adenoviral human wild-type p53 gene (rAd-p53) the protein levels of p53, MDM2, p21, and bax in both Siha and C33a increased. Highest levels of these proteins were detected at 48 hours after transfection. The increased protein expressions were accompanied with inhibition of cell proliferation. At 72 hours after transfection, 12.3% and 5.5% of Siha and C33a cells became apoptotic, respectively. When exposed to 6 Gy of radiation after 48 hours of the transfection, 46.2% and 38.3% apoptotic Siha and C33a cells were detected, respectively; but only 5.6% and 6.3% of apoptotic cells of their un-transfected counterparts detected at 24 hours after the radiation treatment. Conclusions: Wild-type p53 gene transfection can inhibit cell proliferation, promote apoptosis, and sensitize to radiation of both Siha and C33a cells. The effects on Siha cells are stronger.
35
Blagosklonny, Mikhail V., Paraskevi Giannakakou, Malgorzata Wojtowicz, Larisa Y. Romanova, Kenneth B. Ain, Susan E. Bates, and Tito Fojo. "Effects of p53-Expressing Adenovirus on the Chemosensitivity and Differentiation of Anaplastic Thyroid Cancer Cells." Journal of Clinical Endocrinology & Metabolism 83, no. 7 (July 1, 1998): 2516–22. http://dx.doi.org/10.1210/jcem.83.7.4984.
Full textAbstract:
We investigated the p53 status and the ability of exogenous wild-type (wt) p53 to affect chemosensitivity in three anaplastic thyroid carcinoma cell lines (BHT-101, SW-1736, and KAT-4). All three cell lines had nonfunctional p53. Treatment with mitomycin C or adriamycin did not result in accumulation of p53 or induction of p21WAF1/CIP1 or Mdm-2 and did not cause Rb dephosphorylation. BHT-101 and KAT-4 cells had mutant p53. SW-1736 cells were functionally mutant because of marked down-regulation of wt p53 messenger ribonucleic acid, representing a novel mechanism of p53 dysfunction. Infection with a p53-expressing adenovirus (Ad-p53) induced high levels of p21 and Mdm-2 proteins. In BHT-101 cells, induction of p21 and Mdm-2 was evident 10 h after infection. In KAT-4 cells, induction of p21 and Mdm-2 was observed 1 day after infection, and continued to increase over the ensuing 24 h. SW-1736 cells demonstrated intermediate kinetics. Sensitivity to the cytotoxic effect of Ad-p53 paralleled the kinetics of p21/Mdm-2 induction. BHT-101 cells were most sensitive to killing by Ad-p53, with an IC50 of less than 2 multiplicity of infection; SW-1736 cells were intermediate in sensitivity; KAT-4 cells were resistant. All three cell lines became more sensitive to adriamycin after wt p53 expression, with a 10-fold decrease in IC50 values. The latter observation may make a combination of wt p53 and chemotherapeutic drugs an attractive modality for treating anaplastic thyroid cancer.
36
Epenetos, Agamemnon A., Karima Karagussova, and Mahendra Deonarain. "AB1, a novel protein targeting TP53 mutated GI tumors." Journal of Clinical Oncology 40, no. 4_suppl (February 1, 2022): 96. http://dx.doi.org/10.1200/jco.2022.40.4_suppl.096.
Full textAbstract:
96 Background: The tumor suppressor gene TP53 is one of the most frequently deleted or mutated genes in gastrointestinal cancers. Normal p53 regulates several important proteins that control cell cycle, cell death, DNA damage/repair, stemness, differentiation and other key cellular functions. If the TP53 gene is damaged, tumor suppression is severely compromised. On the other hand, and downstream of p53, p21 a potent cyclin-dependent kinase inhibitor (CKI) protein binds and inhibitsthe activity of cyclin - CDK2, - CDK1, and - CDK4/6, thus functioning as a regulator ofcell cycle progression at G 1 and S phase. It can act as de facto p53 repair/ replacement mechanism. We have thus hypothesised that, if we were able to deliver wild type p21 into all p53 mutated cancer cells, it would have a possible therapeutic effect. Methods: We have constructed recombinantly a new fusion protein, named AB1, composed of a cell penetrating protein (antennapedia) ANTP and wild type p21 and tested it in in vitro and in vivo preclinical models prior to clinical studies. AB1 could also be constructed semi-synthetically by conjugating recombinant ANTP chemically to p21 protein. Results: AB1 penetrated and killed p53 mutated cancer cells but did not kill cells that did not have p53 mutations AB1 penetrated but did not kill p53- or p21- wild-type cells. AB1 was not immunogenic in normal New Zealand White rabbits. AB1 was more cytotoxic when administered with conventionally-used chemotherapeutic agents. Conclusions: We have generated a selectively cytotoxic fusion protein against p53 mutated GI cancers which is effective when used as a single agent but more so when used in combination with chemotherapy. The phaseI/II clinical trial will include eligible patients who have p53 mutated GI cancers
37
King, Erin Rebecca, Lisa K. Mullany, JoAnne S. Richards, David Marc Gershenson, and Kwong-Kwok Wong. "Nutlin-3: A novel potential therapeutic in p53 wild-type ovarian carcinomas." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e15583-e15583. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e15583.
Full textAbstract:
e15583 Background: Epithelial ovarian cancer (OC) is a molecularly and clinically heterogeneous disease, yet treatment is the same for all subtypes. Type I carcinomas, including low grade serous, mucinous, clear cell, and endometrioid OCs, are relatively chemoresistant. In contrast, Type II or high grade serous OCs are more aggressive yet responsive to chemotherapy. Molecularly, 96% of high grade serous OCs harbor p53 mutations, whereas Type I carcinomas are more frequently p53 wild-type. Nutlin-3 is a novel therapeutic which inhibits MDM2, activates wild-type p53, and induces apoptosis. We therefore sought to validate nutlin-3 as a therapeutic compound for p53 wild-type OCs. Methods: Two low grade serous, 2 clear cell, 2 endometrioid, 3 mucinous, and 4 high grade serous OC cell lines were treated with varying concentrations of nutlin-3, and proliferation assays were performed. A p53-null cell line was used as a negative control. The cells were then treated with nutlin-3 at their IC50s, and qRT-PCR and Western blot (WB) quantified MDM2, p53, and p21 expression at 24, 48, and 72 hours after treatment. The cell lines were sequenced for p53 mutations in exons 5-8. Results: Responses to nutlin-3 were variable and dependent on p53 mutation status. Low grade and clear cell lines were most sensitive to nutlin-3, endometrioid type were intermediately sensitive, and mucinous were resistant. Two of the four high grade cell lines were sensitive to nutlin-3, both of which were p53 wild-type. Endometrioid and low grade serous cell lines possessing heterozygous p53 mutations were still more sensitive than the p53-null cell line. On qRT-PCR and WB, levels of p53 were decreased after nutlin-3 treatment and were absent in the p53-null cell line. MDM2 and p21 were initially upregulated in sensitive cell lines, but returned to near-baseline levels after 72 hours. In the more resistant cell lines, p21 induction was reduced or absent. Conclusions: Nutlin-3 is a novel potential therapeutic agent for p53 wild-type ovarian carcinoma, and is dependent on an intact p53 pathway with p21 upregulation. Even OC cell lines with heterozygous p53 mutation responded modestly to nutlin-3 treatment. Further investigation of nutlin-3 treatment in ovarian cancer is warranted.
38
Kreis, Louwen, and Yuan. "The Multifaceted p21 (Cip1/Waf1/CDKN1A) in Cell Differentiation, Migration and Cancer Therapy." Cancers 11, no. 9 (August 21, 2019): 1220. http://dx.doi.org/10.3390/cancers11091220.
Full textAbstract:
Loss of cell cycle control is characteristic of tumorigenesis. The protein p21 is the founding member of cyclin-dependent kinase inhibitors and an important versatile cell cycle protein. p21 is transcriptionally controlled by p53 and p53-independent pathways. Its expression is increased in response to various intra- and extracellular stimuli to arrest the cell cycle ensuring genomic stability. Apart from its roles in cell cycle regulation including mitosis, p21 is involved in differentiation, cell migration, cytoskeletal dynamics, apoptosis, transcription, DNA repair, reprogramming of induced pluripotent stem cells, autophagy and the onset of senescence. p21 acts either as a tumor suppressor or as an oncogene depending largely on the cellular context, its subcellular localization and posttranslational modifications. In the present review, we briefly mention the general functions of p21 and summarize its roles in differentiation, migration and invasion in detail. Finally, regarding its dual role as tumor suppressor and oncogene, we highlight the potential, difficulties and risks of using p21 as a biomarker as well as a therapeutic target.
39
Alwhibi, Mona S., Mahmoud I. M. Khalil, Mohamed M. Ibrahim, Gehan A. El-Gaaly, and Ahmed S. Sultan. "Potential Antitumor Activity and Apoptosis Induction ofGlossostemon bruguieriRoot Extract against Hepatocellular Carcinoma Cells." Evidence-Based Complementary and Alternative Medicine 2017 (2017): 1–14. http://dx.doi.org/10.1155/2017/7218562.
Full textAbstract:
Glossostemon bruguieri(moghat) is used as a nutritive and demulcent drink. This study was performed to investigate the antiproliferative effects of moghat root extract (MRE) and its apoptotic mechanism in hepatocellular carcinoma (HCC) cells, HepG2 and Hep3B. MTT assay, morphological changes, apoptosis enzyme linked immunosorbent assay, caspase and apoptotic activation, flow cytometry, and immunoblot analysis were employed. The IC50of MRE for HepG2 (910±6 μg/ml) and for Hep3B (1510±5 μg/ml) induced significant growth-inhibitory effects against HCC cells, with no cytotoxic effect on normal hepatocytes. MRE treatment induced apoptotic effects to HepG2 cells in a caspase-dependent manner and via upregulating p53/p21 and PCNA. The upregulation of p21 was controlled by p53 expression in HepG2 but not in Hep3B despite upregulation of Bax protein in both cell lines. Interestingly, p21 may be a remarkable switch to G1 arrest in HepG2 cells, but not in Hep3B cells. In addition, Fas- and mitochondria-mediated pathways were found to be involved in MRE-induced apoptosis in Hep3B cells. The GC-MS analysis of MRE revealed two major constituents of pharmaceutical importance: the flavonoid apigenin (17.04%) and the terpenoid squalene (11.32%). The data presented in this paper introducesG. bruguierias a promising nontoxic herb with therapeutic potential for HCC. To the authors’ knowledge, the present study provides the first report on the anticancer activity of MRE on HCC cells.
40
Jung, Lee, Kim, Sim, Ahn, Kim, Chang, and Kim. "p53-Dependent Apoptotic Effect of Puromycin via Binding of Ribosomal Protein L5 and L11 to MDM2 and its Combination Effect with RITA or Doxorubicin." Cancers 11, no. 4 (April 24, 2019): 582. http://dx.doi.org/10.3390/cancers11040582.
Full textAbstract:
Among ribosomal proteins essential for protein synthesis, the functions of ribosomal protein L5 (RPL5) and RPL11 still remain unclear to date. Here, the roles of RPL5 and RPL11 were investigated in association with p53/p21 signaling in the antitumor effect of puromycin mainly in HCT116 and H1299 cancer cells. Cell proliferation assays using 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assays and colony formation assays, cell cycle analysis, Reverse transcription polymerase chain reaction (RT-PCR) and Western blotting were performed in cancer cells. Puromycin exerted cytotoxic and anti-proliferative effects in p53 wild-type HCT116 more than in p53 null H1299 cells. Consistently, puromycin increased sub-G1, cleaved Poly (ADP-ribose) polymerase (PARP), activated p53, p21, and Mouse double minute 2 homolog (MDM2), and attenuated expression of c-Myc in HCT116 cells. Notably, puromycin upregulated the expression of RPL5 and RPL11 to directly bind to MDM2 in HCT116 cells. Conversely, deletion of RPL5 and RPL11 blocked the activation of p53, p21, and MDM2 in HCT116 cells. Also, puromycin enhanced the antitumor effect with reactivating p53 and inducing tumor apoptosis (RITA) or doxorubicin in HCT116 cells. These findings suggest that puromycin induces p53-dependent apoptosis via upregulation of RPL5 or RPL11 for binding with MDM2, and so can be used more effectively in p53 wild-type cancers by combination with RITA or doxorubicin.
41
SIVOŇOVÁ, MONIKA KMEŤOVÁ, MARTA VILČKOVÁ, JÁN KLIMENT, SILVIA MAHMOOD, JANA JUREČEKOVÁ, SVETLANA DUŠENKOVÁ, IVETA WACZULÍKOVÁ, PETER SLEZÁK, and DUŠAN DOBROTA. "Association of p53 and p21 polymorphisms with prostate cancer." Biomedical Reports 3, no. 5 (July 27, 2015): 707–14. http://dx.doi.org/10.3892/br.2015.496.
Full text
42
Katsumata, Kenji, Tetsuo Sumi, Keiichiro Yamamoto, Sou Katayanagi, Takashi Murohashi, Kazuhiro Nagashima, Tatsuto Ashizawa, Yasuhisa Koyanagi, Tatsuya Aoki, and Koichirou Katoh. "Relationship between p53, p21 and Apoptosis in Colorectal Cancer." Japanese Journal of Gastroenterological Surgery 33, no. 10 (2000): 1751–57. http://dx.doi.org/10.5833/jjgs.33.1751.
Full text
43
R. Pincus, Matthew, Maly Fenelus, Ehsan Sarafraz-Yazdi, Victor Adler, Wilbur Bowne, and Josef Michl. "Anti-cancer Peptides from Ras-P21 and P53 Proteins." Current Pharmaceutical Design 17, no. 25 (August 1, 2011): 2677–98. http://dx.doi.org/10.2174/138161211797416075.
Full text
44
Roy, Somdutta, and Martin Tenniswood. "Site-specific Acetylation of p53 Directs Selective Transcription Complex Assembly." Journal of Biological Chemistry 282, no. 7 (November 22, 2006): 4765–71. http://dx.doi.org/10.1074/jbc.m609588200.
Full textAbstract:
Histone deacetylase (HDAC) inhibitors are being investigated as possible adjuvant therapies for a number of diseases, including cancer. In addition to stabilization of acetylated histones, HDAC inhibitors stabilize the acetylation of a number of transcription factors, including p53. This study investigates the action of two HDAC inhibitors, CG-1521 and trichostatin A, which stabilize Ac-Lys-373 p53 and Ac-Lys-382 p53, respectively, in LNCaP prostate cancer cells. Real-time PCR demonstrates that CG-1521 induces p21 transcription whereas trichostatin A does not alter the steady state level of p21 mRNA. Co-immunoprecipitation demonstrates that the selective acetylation of p53 directs the recruitment of mutually exclusive coactivator complexes on the p53 response elements in the p21 promoter. Furthermore, the co-activator complexes initiate the recruitment of the components of the basal transcription apparatus to the basal promoter with markedly different outcomes because only Ac-Lys-373 p53 promotes the assembly of the basal transcriptional apparatus on the p21 promoter. These data highlight the profound effects of post-translational modification, including acetylation, on the function of p53. The data also suggest a novel and critically important role for protein acetylation/deacetylation in the assembly of active transcription processes that may be as important as classical phosphorylation/dephosphorylation.
45
Popp, Cristiana, Luciana Nichita, Theodor Voiosu, Alexandra Bastian, Mirela Cioplea, Gianina Micu, Gabriel Pop, et al. "Expression Profile of p53 and p21 in Large Bowel Mucosa as Biomarkers of Inflammatory-Related Carcinogenesis in Ulcerative Colitis." Disease Markers 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/3625279.
Full textAbstract:
Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease that slightly increases the risk of colorectal cancer in patients with long-standing extended disease. Overexpression of p53 and p21 in colonic epithelia is usually detected in UC patients when no dysplasia is histologically seen and it is used by pathologists as a discriminator between regenerative changes and intraepithelial neoplasia, as well as a tissue biomarker useful to predict the risk of evolution toward malignancy. We present a one-year prospective observational study including a cohort of 45 patients with UC; p53 and p21 were evaluated in epithelial cells. p53 was positive in 74 samples revealed in 5% to 90% of epithelial cells, while 63 biopsies had strong positivity for p21 in 5% to 50% of epithelial cells. Architectural distortion was significantly correlated with p53 overexpression in epithelial cells. Thus, we consider that architectural distortion is a good substitute for p53 and p21 expression. We recommend use of p53 as the most valuable tissue biomarker in surveillance of UC patients, identifying the patients with higher risk for dysplasia. Association of p21 is also recommended for a better quantification of risk and for diminishing the false-negative results.
46
Chatterjee, Sunanda J., Ram Datar, David Youssefzadeh, Ben George, Peter J. Goebell, John P. Stein, Lillian Young, et al. "Combined Effects of p53, p21, and pRb Expression in the Progression of Bladder Transitional Cell Carcinoma." Journal of Clinical Oncology 22, no. 6 (March 15, 2004): 1007–13. http://dx.doi.org/10.1200/jco.2004.05.174.
Full textAbstract:
Purpose To determine the combined effects of p53, p21, and pRb alterations in predicting the progression of bladder transitional cell carcinoma. Patients and Methods p53, p21, and pRb expression was examined immunohistochemically on archival radical cystectomy samples from 164 patients with invasive or high-grade recurrent superficial transitional cell carcinoma (TCC; lymph node–negative, 117 patients; lymph node–positive, 47 patients). Median follow-up was 8.6 years. Based on percentage of nuclear reactivity, p53 was considered as wild-type (0% to 10%) or altered (> 10%); p21 was scored as wild-type (>10%) or altered (< 10%); and pRb status was considered wild-type (1% to 50%) or altered (0% or > 50%). Results As individual determinants, the p53, p21, and pRb status were independent predictors of time to recurrence (P < .001, P < .001, and P < .001, respectively), and overall survival (P < .001, P = .002, and P = .001, respectively). By examining these determinants in combination, patients were categorized as group I (no alteration in any determinant, 47 patients), group II (any one determinant altered, 51 patients), group III (any two determinants altered, 42 patients), and group IV (all three determinants altered, 24 patients). The 5-year recurrence rates in these groups were 23%, 32%, 57%, and 93%, respectively (log-rank P < .001), and the 5-year survival rates were 70%, 58%, 33%, and 8%, respectively (log-rank P < .001). After stratifying by stage, the number of altered proteins remained significantly associated with time to recurrence and overall survival. Conclusion This study suggests that alterations in p53, p21, and pRb act in cooperative or synergistic ways to promote bladder cancer progression. Examining these determinants in combination provides additional information above the use of a single determinant alone.
47
Lee, J. E., S. J. Lee, S. E. Namkoong, S. J. Um, J. W. Sull, S. H. Jee, Y. K. You, and J. S. Park. "Gene–gene and gene–environmental interactions of p53, p21, and IRF-1 polymorphisms in Korean women with cervix cancer." International Journal of Gynecologic Cancer 14, no. 1 (January 2004): 118–25. http://dx.doi.org/10.1136/ijgc-00009577-200401000-00016.
Full textAbstract:
BackgroundThe aim of this study was to identify gene–gene and gene–environmental factors affecting cervix carcinogenesis in Korean women.MethodsWe evaluated 530 subjects composed of 185 female cervix cancer patients and 345 normal healthy women. The single nucleotide polymorphisms (SNPs) of p53 codon 72, p21 codon 31, and interferon regulatory factor-1 (IRF-1) intron 6 were evaluated from extracted DNA of peripheral blood with an automatic DNA sequencer. The differences of each SNP, gene–gene and gene–environmental interactions between normal controls and patients were evaluated in the adjusted environmental background.ResultsIn the environmental aspect, the rate of cervix cancer increased in the women with a lower level of education, a younger age at first sexual intercourse and more childbearing. The women who had p53 (Arg/Arg), IRF-1 (T/T), and <6 years of education showed a 14.7-fold increased risk of cervix cancer compared to the women who had p53 (∼Pro), IRF-1 (∼C), and >15 years of education. The women who had p53 (Arg/Arg), p21 (Ser/Ser), and >3 children showed a 6.4-fold increased risk of cervix cancer compared to the women who had p53 (∼Pro), p21 (∼Arg), and no children. The women who had p53 (Arg/Arg), IRF-1 (T/T), and first sexual intercourse before 22 years old showed a 5.5-fold increased risk of cervix cancer compared to the women who had p53 (∼Pro), IRF-1 (∼C), and first sexual intercourse after 26 years old.ConclusionsWe found that the level of education, the age at first intercourse, and the number of children were independent risk factors in cervix carcinogenesis. The specific combinations of p53, p21, and IRF-1 gene–gene and gene–environmental interactions were significantly noted in the cervix carcinogenesis of Korean women.
48
Weglarz, Ludmiła, Izabela Molin, Arkadiusz Orchel, Beata Parfiniewicz, and Zofia Dzierzewicz. "Quantitative analysis of the level of p53 and p21(WAF1) mRNA in human colon cancer HT-29 cells treated with inositol hexaphosphate." Acta Biochimica Polonica 53, no. 2 (May 30, 2006): 349–56. http://dx.doi.org/10.18388/abp.2006_3348.
Full textAbstract:
The aim of this study was to analyze the molecular mechanism of inositol hexaphosphate (InsP(6)) action through which it may inhibit proliferation of colon cancer cells and cell cycle progression. A kinetic study of p53 and p21(WAF1) mRNA increase was performed on human colon cancer HT-29 cells after treatment with 1, 5 and 10 mM InsP(6) for 6, 12, 24 and 48 h. Real-time-QPCR based on TaqMan methodology was applied to analyze quantitatively the transcript levels of these genes. The transcription of beta-actin and GAPDH genes was assessed in parallel to select the control gene with least variability. The 2(-Delta Delta Ct) method was used to analyze the relative changes in gene transcription. InsP(6) stimulated p53 and p21(WAF1) expression at the mRNA level, with the highest increase in p21(WAF1) mRNA occurring at 24 h, i.e., following the highest increase in p53 mRNA observed at 12 h. Based on these studies it may be concluded that the ability of InsP(6) to arrest the cell cycle may be mediated by the transcriptional up-regulation of the p53-responsive p21(WAF1) gene.
49
Liu, X., Y. Xu, Z. Long, H. Zhu, and Y. Wang. "The prognostic significance of apoptosis-related biological markers in Chinese gastric cancer patients." Journal of Clinical Oncology 29, no. 4_suppl (February 1, 2011): 108. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.108.
Full textAbstract:
108 Background: The prognosis varied among the patients with the same stage, therefore there was a need for new prognostic and predictive factors. The aim of this study was to evaluate the relationship of apoptosis-related biological markers such as P21, P27, P53, Bcl-2, Bax, and c-myc, and clinicopathological features and their prognostic value. Methods: From January 1996 to December 2007, 4,426 patients had undergone gastrectomy for gastric cancer at Fudan University Shanghai Cancer Center. Among 501 patients, the expression levels of P21, P27, P53, Bcl-2, Bax, and c-myc were examined by immunohistochemistry. The prognostic value of biological markers and the correlation between biological markers and other clinicopathological factors were investigated. Results: There were 339 males and 162 females (2.09:1) with a mean age of 57. The percentages of positive expression of P21, P27, P53, Bcl-2, Bax, and c-myc were 73%, 25%, 65%, 22%, 43%, and 58%, respectively. There was a strong correlation between P21, P53, Bax, and c-myc expression (p = 0.00). There was significant association between P27, Bcl-2, and Bax expression (p < 0.05). The P21 expression correlated with male (p = 0.00), histological grade (p = 0.00), Borrmann type (p = 0.02), tumor location (p = 0.01); the P53 expression with histological grade (p = 0.01); Bcl-2 expression with pathological stage (p = 0.01); Bax expression with male (p = 0.02), histological grade (p = 0.01), Borrmann type (p = 0.01), tumor location (p = 0.00), lymph node metastasis (p = 0.03), pathological stage (p = 0.01); c-myc expression with Borrmann type (p = 0.00). Bcl-2 expression was related with good survival in univariate analysis (p = 0.01). Multivariate analysis showed that Bcl-2 expression and pathological stage were defined as independent prognostic factors for gastric cancers. There was significant differences of overall 5-year survival rates according to Bcl-2 expression or not in stage III (p = 0.00). Conclusions: The expressionof Bcl-2 was an independent prognostic factor for Chinese patients with gastric cancer; it might be a candidate for the gastric cancer staging system. No significant financial relationships to disclose.
50
Strzeszewska-Potyrała, Anna, Karolina Staniak, Joanna Czarnecka-Herok, Mahmoud-Reza Rafiee, Marcin Herok, Grażyna Mosieniak, Jeroen Krijgsveld, and Ewa Sikora. "Chromatin-Directed Proteomics Identifies ZNF84 as a p53-Independent Regulator of p21 in Genotoxic Stress Response." Cancers 13, no. 9 (April 27, 2021): 2115. http://dx.doi.org/10.3390/cancers13092115.
Full textAbstract:
The p21WAF1/Cip1 protein, encoded by CDKN1A, plays a vital role in senescence, and its transcriptional control by the tumour suppressor p53 is well-established. However, p21 can also be regulated in a p53-independent manner, by mechanisms that still remain less understood. We aimed to expand the knowledge about p53-independent senescence by looking for novel players involved in CDKN1A regulation. We used a chromatin-directed proteomic approach and identified ZNF84 as a novel regulator of p21 in various p53-deficient cell lines treated with cytostatic dose of doxorubicin. Knock-down of ZNF84, an as-yet un-characterized protein, inhibited p21 gene and protein expression in response to doxorubicin, it attenuated senescence and was associated with enhanced proliferation, indicating that ZNF84-deficiency can favor senescence bypass. ZNF84 deficiency was also associated with transcriptomic changes in genes governing various cancer-relevant processes e.g., mitosis. In cells with ZNF84 knock-down we discovered significantly lower level of H2AX Ser139 phosphorylation (γH2AX), which is triggered by DNA double strand breaks. Intriguingly, we observed a reverse correlation between the level of ZNF84 expression and survival rate of colon cancer patients. In conclusion, ZNF84, whose function was previously not recognized, was identified here as a critical p53-independent regulator of senescence, opening possibilities for its targeting in novel therapies of p53-null cancers.