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Hypoxia upregulates Rab11-family interacting protein 4 through HIF-1α to promote the metastasis of hepatocellular carcinoma

Oncogene volume 34, pages 6007–6017 (2015)Cite this article

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Abstract

Hypoxic microenvironment is a powerful driving force for the invasion and metastasis of hepatocellular carcinoma (HCC). Hypoxia-inducible factor 1α (HIF-1α), as a crucial regulator of transcriptional responses to hypoxia, induces the expression of multiple target genes involved in different steps of HCC metastatic process. It is critical to find target genes associated with metastasis under hypoxia for shedding new light on molecular mechanism of HCC metastasis. In this study, we uncovered that hypoxia could induce the upregulation of Rab11-family interacting protein 4 (Rab11-FIP4) and activation of Rab11-FIP4 promoter by HIF-1α. The overexpression of Rab11-FIP4 significantly enhanced the mobility and invasiveness of HCC cells in vitro, also contributed to distant lung metastasis in vivo, whereas silencing of Rab11-FIP4 decreased the ability of migration and invasion in HCC cells in vitro and suppressed lung metastasis in vivo. Rab11-FIP4 facilitated HCC metastasis through the phosphorylation of PRAS40, which was regulated by mTOR. Furthermore, the expression level of Rab11-FIP4 was significantly increased in HCC tissues and high expression of Rab11-FIP4 was closely correlated with vascular invasion and poor prognosis in HCC patients. A markedly positive correlation between the expression of Rab11-FIP4 and HIF-1α was observed in HCC tissues and combination of Rab11-FIP4 and HIF-1α was a more valuable predictor of poor prognosis for HCC patients. In conclusion, Rab11-FIP4 is a target gene of HIF-1α and has a pro-metastatic role in HCC, suggesting that Rab11-FIP4 may be a promising candidate target for HCC treatment.

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Abbreviations

HCC:

hepatocellular carcinoma

HIF-1α:

hypoxia-inducible factor 1α

PHDs:

prolyl hydroxylases

HREs:

hypoxia-responsive elements

CoCl2:

cobalt chloride

Rab11-FIP4:

Rab11-family interacting protein 4

OS:

overall survival

DFS:

disease-free survival

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Acknowledgements

This work was supported by grants from National Key Sci-Tech Special Project of China (2012ZX10002011-004), National Natural Science Foundation of China (81201627 and 81371883), Shanghai Municipal Program of International Cooperation in Science and Technology (12410709800), Research Fund for the Doctoral Program of Higher Education of China (20120073110091), Key Basic Research Program of Shanghai Committee of Science and Technology (11JC1412201), Grant from the State Key Laboratory of Oncogenes and Related Genes (91-1201, 91-1305), Doctoral Innovation Fund of Shanghai Jiao Tong University School of Medicine (BXJ201243) and Key Discipline and Specialty Foundation of Shanghai Municipal Commission of Health and Family Planning.

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Author notes

  1. F Hu, X Deng, X Yang and H Jin: These authors contributed equally to this work.

Authors and Affiliations

  1. Shanghai Medical College of Fudan University, Shanghai, China

    F Hu, X Deng & T Ge

  2. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    F Hu, X Deng, H Jin, D Gu, C Wang, Y Zhang, X Huo, Q Shen, Q Luo, T Ge, F Zhao, W Chu, H Shu, M Yao & W Qin

  3. Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical College, Fudan University, Shanghai, China

    X Yang & J Fan

  4. Department of Pathophysiology, Guangdong Medical College, Dongguan, China

    D Gu

  5. Basic Medical Research Centre, Medical College of Nantong University, Nantong, China

    X Lv & F Zhao

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Correspondence to J Fan or W Qin.

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Hu, F., Deng, X., Yang, X. et al. Hypoxia upregulates Rab11-family interacting protein 4 through HIF-1α to promote the metastasis of hepatocellular carcinoma. Oncogene 34, 6007–6017 (2015). https://doi.org/10.1038/onc.2015.49

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