p21<sup>Waf1/Cip1</sup>revisited: oncogenic function in hepatocellular carcinoma

Goldenberg, Daniel; Eferl, Robert

doi:10.1136/gutjnl-2013-306343

Cited by 6 publications

(5 citation statements)

References 9 publications

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“…In contrast, it through mediating p21 downregulation contributed to the progression of gastric carcinoma. 25,42 The tumor-specificity of miRNAs warns us that we should undergo relevant in vitro/vivo experiments before carrying out miRNA therapy.…”

Section: Discussionmentioning

confidence: 99%

“…24 p2 1 was demonstrated to be activated by dsP21-322 in an RNAa manner and thus plays an anti-tumor role in amount of human tumors. 25–27 In previous study, we found that three miRNAs (miR-1236, miR-370, and miR-1180) can upregulate p21 gene expression in bladder cancer through binding p21 promoter. 19 However, whether miRNAs can upregulate p21 expression in diverse human cancer cells is unclear.…”

Section: Introductionmentioning

confidence: 97%

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Effects of miR-1236-3p and miR-370-5p on activation of p21 in various tumors and its inhibition on the growth of lung cancer cells

Liu

et al. 2017

Tumour Biol.

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The mechanism of dsRNA-induced gene activation (RNAa) is being gradually unveiled. The plentiful evidence that it existed in mammalian species other than human demonstrated that dsRNA-mediated RNAa is a conservative phenomenon. Simultaneously, accumulating evidence suggested that microRNAs could activate gene expression by targeting promoter. Nevertheless, it is ambiguous whether microRNA-induced gene activation in different human cells is a common phenomenon. The study we performed verified that miR-1236-3p (miR-1236) and miR-370-5p can activate p21 expression in bladder cancer (BCa) T24, EJ cells, and non-small-cell lung carcinoma A549 cells, while in hepatocellular HepG2 cells both microRNAs cannot effectively induce the expression of P21 (p21). In pancreatic cancer PANC-1 cells, only miR-370-5p had the potent abilities to induce p21 expression rather than miR-1236-3p. Unlike microRNA-mediated RNA activation, we can observe that dsP21-322 significantly activated p21 in above cells. Besides, we demonstrated that miR-1236 and miR-370 inhibited cyclin D1-CDK4/CDK6 pathway while upregulated E-cadherin expression by upregulation of p21. Overexpression of these two microRNAs in A549 induced cell-cycle arrest and cell senescence, delayed cell proliferation and colony formation, and inhibited migration and invasion. In conclusion, microRNA-mediated RNAa depends on the cell context, and miR-1236 and miR-370 can inhibit non-small-cell lung carcinoma cell growth by upregulating p21 expression in vitro.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Effects of miR-1236-3p and miR-370-5p on activation of p21 in various tumors and its inhibition on the growth of lung cancer cells

Liu

et al. 2017

Tumour Biol.

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“…Clinical characteristics such as vascular invasion, Barcelona Clinic Liver Cancer (BCLC) staging, tumor size, alpha-fetal protein (AFP), morphological and pathological features are traditionally the most important prognostic factors. Those related studies that had be conducted before had shown that the expression of p53 [also known as tumor protein p53 (TP53)], p21 [cyclin dependent kinase inhibitor 1A (CDKN1A)], nm23 [also known as nucleoside diphosphate kinase 1 (NME1)] and VEGF [also known as vascular endothelial growth factor A (VEGFA)] could reflect the prognosis of liver cancer by immunohistochemical techniques [11][12][13][14]. p53 protein, a protein suppressing tumor, has response to diverse cellular stresses for regulating the expression of target genes, and thus induces senescence, apoptosis, cell cycle arrest, DNA repair, or changes in metabolism.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive investigation of p53, p21, nm23, and VEGF expression in hepatitis B virus-related hepatocellular carcinoma overall survival after hepatectomy

et al. 2020

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Objective:The goal of our current study is to assess the immunohistochemical of p53, p21, nm23, and VEGF expression in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) prognosis after hepatectomy, as well as the prospective molecular mechanisms of prognostic indicator. Methods: There were 419 HBV-related HCC patients who were from southern China of Guangxi province and were used to evaluate the immunohistochemical expression for these biomarkers in prognosis. A genome-wide expression microarray dataset of HBV-related HCC were obtained from GSE14520. Results: In our study, the expression of p53, p21, and nm23 in cancer tissues of patients with hepatitis B-related hepatocellular carcinoma did not affected the clinical outcome of 2 years, 5 years or overall. Patients with high expression of VEGF had a worse overall survival after 2 years of surgery than patients with low expression (adjusted P=0.040, adjusted HR = 1.652, 95% CI = 1.024-2.665). Survival analysis of VEGF in GSE14520 cohort also demonstrated that VEGF mRNA expression also significantly associated with HBV-related HCC OS (adjusted P=0.035, adjusted HR =1.651, 95% CI =1.035-2.634). The prospective molecular mechanisms by co-expression analysis suggested that VEGF might be correlated to regulation of cell proliferation, cell growth and apoptotic process, Rap1 signaling pathway, HIF-1 signaling pathway, PPAR signaling pathway, cell cycle. Whereas the GSEA suggested that VEGF might involve in the regulation of HIF and HIF1A pathway, and TP53 regulation pathway. Conclusion: Our findings suggested that VEGF might be a prognostic indicator of HBV-related HCC, and we also identified the VEGF prospective molecular mechanisms through the whole genome co-expression and GSEA approaches.

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“…High Mat1a, as well as high SAM level, is a marker of quiescent differentiated hepatocytes [ 14 ]; thus, Mat1a can be considered as a classical tumor suppressor in HCC [ 47 ]. Although p21 and Cebpa proteins both were traditionally considered as tumor suppressors [ 48 ], [ 49 ], recent new evidences demonstrate that in some cases they may be pro-oncogenic as well [ 50 – 52 ]. Thus, in mouse HCC models, including the Mdr2-KO model, it was shown that p21 either suppressed or promoted HCC development depending on either strong or moderate liver injury, respectively [ 53 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

Tumor-suppressive effect of S-adenosylmethionine supplementation in a murine model of inflammation-mediated hepatocarcinogenesis is dependent on treatment longevity

et al. 2017

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Chronic inflammation precedes the majority of hepatocellular carcinoma (HCC) cases. We investigated the chemopreventive potential of S-adenosylmethionine (SAM), an essential donor for all methylation reactions in the cell, at the late precancerous stage of HCC development using the Mdr2-knockout (Mdr2-KO, Abcb4−/−) mice, a model of inflammation-mediated hepatocarcinogenesis. Previously, we revealed down-regulation of the genes regulating SAM metabolism in the liver of these mice at the precancerous stages. Now, we have supplied Mdr2-KO mice at the late precancerous stage with SAM during either a short-term (17 days) or a long-term (51 days) period and explored the effects of such supplementation on tumor development, DNA methylation and gene expression in the liver. The short-term SAM supplementation significantly decreased the number of small tumor nodules, proliferating hepatocytes and the total DNA methylation level, while it increased expression of the tumor suppressor proteins Mat1a and p21. Surprisingly, the long-term SAM supplementation did not affect tumor growth and hepatocyte proliferation, while it increased the total liver DNA methylation. Our results demonstrate that the short-term SAM supplementation in the Mdr2-KO mice inhibited liver tumor development potentially by increasing multiple tumor suppressor mechanisms resulting in cell cycle arrest. The long-term SAM supplementation resulted in a bypass of the cell cycle arrest in this HCC model by a yet unknown mechanism.

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p21^Waf1/Cip1revisited: oncogenic function in hepatocellular carcinoma

Cited by 6 publications

References 9 publications

Effects of miR-1236-3p and miR-370-5p on activation of p21 in various tumors and its inhibition on the growth of lung cancer cells

Effects of miR-1236-3p and miR-370-5p on activation of p21 in various tumors and its inhibition on the growth of lung cancer cells

Comprehensive investigation of p53, p21, nm23, and VEGF expression in hepatitis B virus-related hepatocellular carcinoma overall survival after hepatectomy

Tumor-suppressive effect of S-adenosylmethionine supplementation in a murine model of inflammation-mediated hepatocarcinogenesis is dependent on treatment longevity

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p21Waf1/Cip1revisited: oncogenic function in hepatocellular carcinoma

Cited by 6 publications

References 9 publications

Effects of miR-1236-3p and miR-370-5p on activation of p21 in various tumors and its inhibition on the growth of lung cancer cells

Effects of miR-1236-3p and miR-370-5p on activation of p21 in various tumors and its inhibition on the growth of lung cancer cells

Comprehensive investigation of p53, p21, nm23, and VEGF expression in hepatitis B virus-related hepatocellular carcinoma overall survival after hepatectomy

Tumor-suppressive effect of S-adenosylmethionine supplementation in a murine model of inflammation-mediated hepatocarcinogenesis is dependent on treatment longevity

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p21^Waf1/Cip1revisited: oncogenic function in hepatocellular carcinoma