Role of cyclophilin B in tumorigenesis and cisplatin resistance in hepatocellular carcinoma in humans

Authors

  • Yeonghwan Kim,

    1. Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea
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  • Miran Jang,

    1. Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea
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  • Sangbin Lim,

    1. Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea
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  • Hyeran Won,

    1. Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea
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  • Kyung-Sik Yoon,

    1. Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea
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  • Jae-Hoon Park,

    1. Department of Pathology, School of Medicine, Kyung Hee University, Seoul, Korea
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  • Hyo Jong Kim,

    1. Department of Gastroenterology and Hepatology, School of Medicine, Kyung Hee University, Seoul, Korea
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  • Byung-Ho Kim,

    1. Department of Gastroenterology and Hepatology, School of Medicine, Kyung Hee University, Seoul, Korea
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  • Won-Sang Park,

    1. Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
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  • Joohun Ha,

    1. Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea
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  • Sung-Soo Kim

    Corresponding author
    1. Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea
    • Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, #1 Hoegi-dong, Dongdaemoon-gu, Seoul 130-701, Republic of Korea
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    • Fax: +82 2 959 8168


  • Potential conflict of interest: Nothing to report.

  • This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST; to S.S.K.) (No. 20100028333 and No. 20110030721).

Abstract

Cyclophilin B (CypB) performs diverse roles in living cells, but its role in hepatocellular carcinoma (HCC) is largely unclear. To reveal its role in HCC, we investigated the induction of CypB under hypoxia and its functions in tumor cells in vitro and in vivo. Here, we demonstrated that hypoxia-inducible factor 1α (HIF-1α) induces CypB under hypoxia. Interestingly, CypB protected tumor cells, even p53-defective HCC cells, against hypoxia- and cisplatin-induced apoptosis. Furthermore, it regulated the effects of HIF-1α, including those in angiogenesis and glucose metabolism, via a positive feedback loop with HIF-1α. The tumorigenic and chemoresistant effects of CypB were confirmed in vivo using a xenograft model. Finally, we showed that CypB is overexpressed in 78% and 91% of the human HCC and colon cancer tissues, respectively, and its overexpression in these cancers reduced patient survival. Conclusions: These results indicate that CypB induced by hypoxia stimulates the survival of HCC via a positive feedback loop with HIF-1α, indicating that CypB is a novel candidate target for developing chemotherapeutic agents against HCC and colon cancer. (HEPATOLOGY 2011;).

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