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P16 reactivation induces anoikis and exhibits antitumour potency by downregulating Akt/survivin signalling in hepatocellular carcinoma cells
  1. Huanzhang Hu1,2,
  2. Zhigang Li3,
  3. Jie Chen3,
  4. Duanming Wang1,4,
  5. Juming Ma5,
  6. Weiguo Wang5,
  7. Jiang Li1,
  8. Hongping Wu1,
  9. Linfang Li1,
  10. Mengchao Wu1,
  11. Qijun Qian1,
  12. Jingbo Chen4,
  13. Changqing Su1
  1. 1Laboratory of Viral & Gene Therapy, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China
  2. 2Department of Hepatobiliary Surgery, Fuzhou General Hospital of Nanjing Miltary Area, Fujian, China
  3. 3Department of Hematology & Cardiothoracic Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, China
  4. 4College of Animal Science and Technology, Shihezi University, Xinjiang, China
  5. 5Department of Internal Medicine, 117th Hospital of Nanjing Military Area, Hangzhou, China
  1. Correspondence to Prof Changqing Su, Laboratory of Viral & Gene Therapy, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, No. 225 Changhai Road, Shanghai 200438, China; suchangqing{at}gmail.com

Abstract

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.

  • P16 gene
  • anoikis
  • cell cycle
  • Akt/survivin signalling
  • hepatocellular carcinoma
  • apoptosis
  • cell signalling
  • gene therapy

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Footnotes

  • Funding This work was supported by grants from the National Significant Science and Technology Special Projects of New Drugs Creation (No. 2009ZX09102-235) and the National Natural Scientific Foundation of China (No. 81071866, 30973469).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Research Ethics Committee of the Second Military Medical University.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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