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Upregulation of the oncoprotein SET determines poor clinical outcomes in hepatocellular carcinoma and shows therapeutic potential

Oncogene volume 35, pages 4891–4902 (2016)Cite this article

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Abstract

The SET protein is a potent inhibitor of protein phosphatase 2A (PP2A). Here, we report the oncogenic role of SET in hepatocarcinogenesis, clinical aggressiveness and anti-hepatocellular carcinoma (HCC) therapeutics. By analyzing samples obtained from 147 HCC patients, we found that SET overexpression was detected specifically in 30.6% HCC tumor samples, and was significantly associated with worse clinical features and high p-Akt expression in HCC tumors. Co-expression of SET and Akt predicted shorter post-operative recurrence-free survival in this cohort (P=0.045). Furthermore, SET was significantly associated with cell growth and hepatosphere formation. To elucidate the anti-HCC potential of targeting SET, we generated a novel SET antagonist, EMQA (N4-(3-ethynylphenyl)-6,7-dimethoxy-N2-(4-phenoxyphenyl) quinazoline-2,4-diamine). EMQA enhanced PP2A activity via disrupting SET-PP2Ac (catalytic domain of PP2A) binding in HCC cells, which restored PP2A-mediated p-Akt downregulation and promoted HCC cell death. In HCC cells or recombinant proteins expressing the N- and C- truncated forms of SET, only the C-terminal SET was required for EMQA targeting. Furthermore, combining sorafenib and EMQA showed good synergism in inhibiting HCC survival. Our findings suggested the oncogenic role of SET and the adverse prognostic value of SET overexpression in HCC. This alteration defines a subgroup of HCC patients who could benefit from SET antagonists, such as EMQA.

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Acknowledgements

This study is supported by grant MOST-104-3113-B-076-001 from the Ministry of Science and Technology and grant 104DHA0100480 and V105B-015 from Taipei Veterans General Hospital, and partial support from Taiwan Clinical Oncology Research Foundation, Taipei Veterans General Hospital-National Yang-Ming University Excellent Physician Scientists Cultivation Program.

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan

    M-H Hung

  2. Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    M-H Hung

  3. Program in Molecular Medicine, School of Life Science, National Yang-Ming University, Taipei, Taiwan

    M-H Hung

  4. School of Medicine, National Yang-Ming University, Taipei, Taiwan

    M-H Hung

  5. School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Y-L Chen

  6. Department of Surgery, Changhua Christian Hospital, Chang-Hua, Taiwan

    Y-L Chen

  7. Department of Pathology, Show Chwan Memorial Hospital, Chang-Hua, Taiwan

    P-Y Chu

  8. School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan

    P-Y Chu

  9. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

    C-T Shih, H-C Yu, W-T Tai & K-F Chen

  10. National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan

    W-T Tai & K-F Chen

  11. Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan

    C-W Shiau

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Hung, MH., Chen, YL., Chu, PY. et al. Upregulation of the oncoprotein SET determines poor clinical outcomes in hepatocellular carcinoma and shows therapeutic potential. Oncogene 35, 4891–4902 (2016). https://doi.org/10.1038/onc.2016.21

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