| P16 reactivation induces anoikis and exhibits antitumour potency by downregulating Akt/survivin signalling in hepatocellular carcinoma cells. | |
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MedLine Citation:
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PMID: 20971978 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Hepatocellular carcinoma (HCC) is one of the most malignant tumours with high rate of recurrence and metastasis. In HCC, deficiency of the P16/CDK4/Rb pathway is a frequent molecular event, and transferring the P16 gene into cancer cells can induce cell cycle arrest and apoptosis, suggesting that the P16 gene is a good target in cancer gene therapy. The previous study demonstrated that P16 re-expression mediated by adenovirus within cancer cells can induce cell apoptosis and exert potent antitumour efficacy in cancer xenografts in nude mice. However, the molecular mechanism of P16-induced apoptosis in cancer cells is not clear yet. In this resulting study, we found that P16 re-expression can downregulate survivin expression in HCC cells. As a member of the inhibitors of the apoptotic gene family, survivin has been reported to be overexpressed in most common human cancers and present multiple physiological and pathological functions including cell cycle control, inhibition of cell apoptosis, regulation of cell division and induction of angiogenesis, etc. Further investigation found that P16 reactivation led to a decrease of phosphorylated Akt on Thr308 and phosphorylated survivin on Thr34, then downregulated survivin expression. The P16-mediated decrease of nuclear survivin in cancer cells limited CDK4 import into nuclei, which restrained CDK4 functions of promoting cell proliferation, then exhibited the effect of cell cycle arrest and induction of detachment-induced apoptosis (anoikis). The antitumor potency of P16 by downregulating the Akt/survivin signalling was also demonstrated in HCC xenograft models in nude mice. This new insight into P16 function would help in designing better strategies for cancer gene therapy. |
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Authors:
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Huanzhang Hu; Zhigang Li; Jie Chen; Duanming Wang; Juming Ma; Weiguo Wang; Jiang Li; Hongping Wu; Linfang Li; Mengchao Wu; Qijun Qian; Jingbo Chen; Changqing Su |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-22 |
Journal Detail:
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Title: Gut Volume: 60 ISSN: 1468-3288 ISO Abbreviation: Gut Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-04-05 Completed Date: 2011-07-22 Revised Date: 2012-06-25 |
Medline Journal Info:
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Nlm Unique ID: 2985108R Medline TA: Gut Country: England |
Other Details:
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Languages: eng Pagination: 710-21 Citation Subset: AIM; IM |
Affiliation:
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Laboratory of Viral & Gene Therapy, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai 200438, China. suchangqing@gmail.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anoikis / genetics Cell Cycle / genetics Cell Nucleus / metabolism Cyclin-Dependent Kinase 4 / metabolism Cyclin-Dependent Kinase Inhibitor p16 / metabolism Down-Regulation Gene Expression Regulation, Neoplastic Gene Knockdown Techniques / methods Gene Therapy / methods Genes, p16* Humans Inhibitor of Apoptosis Proteins / metabolism Liver Neoplasms, Experimental / genetics*, metabolism, pathology, prevention & control Mice Mice, Nude Phosphorylation Proto-Oncogene Proteins c-akt / metabolism Signal Transduction / genetics Transcriptional Activation Tumor Cells, Cultured Xenograft Model Antitumor Assays |
| Chemical | |
Reg. No./Substance:
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0/BIRC5 protein, human; 0/Cyclin-Dependent Kinase Inhibitor p16; 0/Inhibitor of Apoptosis Proteins; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.22/CDK4 protein, human; EC 2.7.11.22/Cyclin-Dependent Kinase 4 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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