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Hepatitis B virus X protein reduces the stability of Nrdp1 to up-regulate ErbB3 in hepatocellular carcinoma cells

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Tumor Biology

Abstract

Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) is the most widespread type of liver cancer. However, the underlying mechanism of HCC tumorigenesis is very intricate and HBV-encoded X protein (HBx) has been reported to play a key role in this process. It has been reported that HBx up-regulates the transcription of ErbB3. However, it remains unclear whether HBx can regulate ErbB3 expression at post-translational modification level. In this study, we showed that HBx interacts with ubiquitin ligase Nrdp1 (neuregulin receptor degradation protein 1) and decreases its stability, which results in the up-regulation of ErbB3 and promotion of HCC cells. Moreover, the expression of ErbB3 was almost undetectable in normal liver tissues but was relative abundant in HCC tissues, and the level of ErbB3 and Nrdp1 significantly showed a negative correlation in HCC tissues. Taken together, these findings suggest that HBx promotes the progression of HCC by decreasing the stability of Nrdp1, which results in up-regulation of ErbB3, suggesting that ErbB3 may be a target for HCC therapy.

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References

  1. Benhenda S, Cougot D, Buendia MA, Neuveut C. Hepatitis B virus X protein molecular functions and its role in virus life cycle and pathogenesis. Adv Cancer Res. 2009;103:75–109.

    Article  CAS  PubMed  Google Scholar 

  2. Rawat S, Bouchard MJ. The hepatitis B virus (HBV) HBx protein activates AKT to simultaneously regulate HBV replication and hepatocyte survival. J Virol. 2015;89:999–1012.

    Article  PubMed  Google Scholar 

  3. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–37.

    Article  CAS  PubMed  Google Scholar 

  4. Fuller SJ, Sivarajah K, Sugden PH. ErbB receptors, their ligands, and the consequences of their activation and inhibition in the myocardium. J Mol Cell Cardiol. 2008;44:831–54.

    Article  CAS  PubMed  Google Scholar 

  5. Ettinger DS. Clinical implications of EGFR expression in the development and progression of solid tumors: focus on non-small cell lung cancer. Oncologist. 2006;11:358–73.

    Article  CAS  PubMed  Google Scholar 

  6. Berg M, Soreide K. EGFR and downstream genetic alterations in KRAS/BRAF and PI3K/AKT pathways in colorectal cancer: implications for targeted therapy. Discov Med. 2012;14:207–14.

    PubMed  Google Scholar 

  7. Troiani T, Martinelli E, Capasso A, Morgillo F, Orditura M, De Vita F, et al. Targeting EGFR in pancreatic cancer treatment. Curr Drug Targets. 2012;13:802–10.

    Article  CAS  PubMed  Google Scholar 

  8. Okines A, Cunningham D, Chau I. Targeting the human EGFR family in esophagogastric cancer. Nat Rev Clin Oncol. 2011;8:492–503.

    Article  CAS  PubMed  Google Scholar 

  9. Garcia I, Vizoso F, Martin A, Sanz L, Abdel-Lah O, Raigoso P, et al. Clinical significance of the epidermal growth factor receptor and HER2 receptor in resectable gastric cancer. Ann Surg Oncol. 2003;10:234–41.

    Article  CAS  PubMed  Google Scholar 

  10. Losert A, Lotsch D, Lackner A, Koppensteiner H, Peter-Vorosmarty B, Steiner E, et al. The major vault protein mediates resistance to epidermal growth factor receptor inhibition in human hepatoma cells. Cancer Lett. 2012;319:164–72.

    Article  CAS  PubMed  Google Scholar 

  11. Hsieh SY, He JR, Yu MC, Lee WC, Chen TC, Lo SJ, et al. Secreted ERBB3 isoforms are serum markers for early hepatoma in patients with chronic hepatitis and cirrhosis. J Proteome Res. 2011;10:4715–24.

    Article  CAS  PubMed  Google Scholar 

  12. Chen JY, Chen YJ, Yen CJ, Chen WS, Huang WC. HBx sensitizes hepatocellular carcinoma cells to lapatinib by up-regulating ErbB3. Oncotarget. 2015;7:473–89.

    PubMed Central  Google Scholar 

  13. Shi H, Gao Y, Tang Y, Wu Y, Gong H, Du J, et al. CacyBP/SIP protein is important for the proliferation of human glioma cells. IUBMB Life. 2014;66:286–91.

    Article  CAS  PubMed  Google Scholar 

  14. Shi H, Zheng B, Wu Y, Tang Y, Wang L, Gao Y, et al. Ubiquitin ligase Siah1 promotes the migration and invasion of human glioma cells by regulating HIF-1alpha signaling under hypoxia. Oncol Rep. 2015;33:1185–90.

    CAS  PubMed  Google Scholar 

  15. Ryu WS. Molecular aspects of hepatitis B viral infection and the viral carcinogenesis. J Biochem Mol Biol. 2003;36:138–43.

    CAS  PubMed  Google Scholar 

  16. Bouchard MJ, Schneider RJ. The enigmatic X gene of hepatitis B virus. J Virol. 2004;78:12725–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Qiu XB, Goldberg AL. Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3. Proc Natl Acad Sci U S A. 2002;99:14843–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Diamonti AJ, Guy PM, Ivanof C, Wong K, Sweeney C, Carraway KL. An RBCC protein implicated in maintenance of steady-state neuregulin receptor levels. Proc Natl Acad Sci U S A. 2002;99:2866–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wu X, Yen L, Irwin L, Sweeney C, Carraway KL. Stabilization of the E3 ubiquitin ligase Nrdp1 by the deubiquitinating enzyme USP8. Mol Cell Biol. 2004;24:7748–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mujoo K, Choi BK, Huang Z, Zhang N, An Z. Regulation of ERBB3/HER3 signaling in cancer. Oncotarget. 2014;5:10222–36.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Dhanasekaran R, Limaye A, Cabrera R. Hepatocellular carcinoma: current trends in worldwide epidemiology, risk factors, diagnosis, and therapeutics. Hepat Med. 2012;4:19–37.

    PubMed  PubMed Central  Google Scholar 

  22. Nguyen VT, Law MG, Dore GJ. Hepatitis B-related hepatocellular carcinoma: epidemiological characteristics and disease burden. J Viral Hepat. 2009;16:453–63.

    Article  CAS  PubMed  Google Scholar 

  23. Neo SY, Leow CK, Vega VB, Long PM, Islam AF, Lai PB, et al. Identification of discriminators of hepatoma by gene expression profiling using a minimal dataset approach. Hepatology. 2004;39:944–53.

    Article  CAS  PubMed  Google Scholar 

  24. Hsieh SY, He JR, Hsu CY, Chen WJ, Bera R, Lin KY, et al. Neuregulin/erythroblastic leukemia viral oncogene homolog 3 autocrine loop contributes to invasion and early recurrence of human hepatoma. Hepatology. 2011;53:504–16.

    Article  CAS  PubMed  Google Scholar 

  25. Yen L, Cao Z, Wu X, Ingalla ER, Baron C, Young LJ, et al. Loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor cell growth. Cancer Res. 2006;66:11279–86.

    Article  CAS  PubMed  Google Scholar 

  26. Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995;19:183–232.

    Article  CAS  PubMed  Google Scholar 

  27. Sithanandam G, Anderson LM. The ERBB3 receptor in cancer and cancer gene therapy. Cancer Gene Ther. 2008;15:413–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer. 2009;9:463–75.

    Article  CAS  PubMed  Google Scholar 

  29. Schoeberl B, Pace EA, Fitzgerald JB, Harms BD, Xu L, Nie L, et al. Therapeutically targeting ErbB3: a key node in ligand-induced activation of the ErbB receptor-PI3K axis. Sci Signal. 2009;2:ra31.

    Article  PubMed  Google Scholar 

  30. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039–43.

    Article  CAS  PubMed  Google Scholar 

  31. Hynes NE, MacDonald G. ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol. 2009;21:177–84.

    Article  CAS  PubMed  Google Scholar 

  32. Pan YS, Lee YS, Lee YL, Lee WC, Hsieh SY. Differentially profiling the low-expression transcriptomes of human hepatoma using a novel SSH/microarray approach. BMC Genomics. 2006;7:131.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Sheng Q, Liu X, Fleming E, Yuan K, Piao H, Chen J, et al. An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells. Cancer Cell. 2010;17:298–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Schoeberl B, Faber AC, Li D, Liang MC, Crosby K, Onsum M, et al. An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. Cancer Res. 2010;70:2485–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lu H, Li H, Mao D, Zhu Z, Sun H. Nrdp1 inhibits growth of colorectal cancer cells by nuclear retention of p27. Tumour Biol. 2014;35:8639–43.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Foundation of Jiangsu Provincial Health Department (H201429), the Foundation of Xuzhou science and Technology Bureau (KC14SX011), the National Natural Science Foundation of China (81201264), the China Postdoctoral Science Foundation (2014 M551662), and the Jiangsu Planned Projects for Postdoctoral Research Funds (1402191C).

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    Authors and Affiliations

    1. Department of general surgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, 221002, China

      Kuan Cao, Quan Wen, Bin Zhang, Xinyu Zhou & Renhao Wang

    2. Insititute of Nervous System Diseases, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou, Jiangsu, 221002, China

      Tianjin Tang, Tong Cao, Bin Wang & Hengliang Shi

    3. The Graduate School, Xuzhou Medical College, Xuzhou, Jiangsu, China

      Kuan Cao, Hui Gong, Zhichao Qiu, Tianjin Tang, Xinyu Zhou, Tong Cao, Bin Wang & Hengliang Shi

    4. Neurosurgery Department of Jiangsu Haimen People’s Hospital, Nantong, China

      Hui Gong & Zhichao Qiu

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    1. Kuan Cao
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    Correspondence to Hengliang Shi or Renhao Wang.

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    Kuan Cao and Hui Gong contributed equally to this work.

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    Cao, K., Gong, H., Qiu, Z. et al. Hepatitis B virus X protein reduces the stability of Nrdp1 to up-regulate ErbB3 in hepatocellular carcinoma cells. Tumor Biol. 37, 10375–10382 (2016). https://doi.org/10.1007/s13277-016-4936-y

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