Hepatitis B virus X protein (HBx) enhances centrosomal P4.1-associated protein (CPAP) expression to promote hepatocarcinogenesis

Chia Jui Yen, Shu Ting Yang, Ruo Yu Chen, Wenya Huang, Kazuaki Chayama, Ming Hao Lee, Shiang Jie Yang, Hong Sheng Lai, Hsin Yi Yen, Yu Wei Hsiao, Ju Ming Wang, Yih Jyh Lin, Liang Yi Hung

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4 Citations (Scopus)

Abstract

Background: Our previous report suggested that centrosomal P4.1-associated protein (CPAP) is required for Hepatitis B virus (HBV) encoded non-structure protein X (HBx)-mediated nuclear factor kappa light chain enhancer of activated B cells (NF-andkappa;B) activation. CPAP is overexpressed in HBV-associated hepatocellular carcinoma (HCC); however, the interaction between CPAP and HBx in HBV-HCC remains unclear. Methods: The mRNA expression of CPAP and HBx was analyzed by quantitative-PCR (Q-PCR). NF-andkappa;B transcriptional activity and CPAP promoter activity were determined using a reporter assay in Huh7 and Hep3B cells. Immunoprecipitation (IP) and in situ proximal ligation assay (PLA) were performed to detect the interaction between CPAP and HBx. Chromatin-IP was used to detect the association of cAMP response element binding protein (CREB) and HBx with the CPAP promoter. Cell proliferation was measured using cell counting kit CCK-8, Bromodeoxyuridine (5-bromo-2andprime;-deoxyuridine, BrdU) incorporation, and clonogenic assays. The tumorigenic effects of CPAP were determined using xenograft animal models. Results: HBx can transcriptionally up-regulate CPAP via interacting with CREB. Overexpressed CPAP directly interacted with HBx to promote HBx-mediated cell proliferation and migration; SUMO modification of CPAP was involved in interacting with HBx. Knocked-down expression of CPAP decreased the HBx-mediated tumorigenic effects, including cytokines secretion. Interestingly, overexpressed CPAP maintained the HBx protein stability in an NF-andkappa;B-dependent manner; and the expression levels of CPAP and HBx were positively correlated with the activation status of NF-andkappa;B in HCC. Increased expression of CPAP and CREB mRNAs existed in the high-risk group with a lower survival rate in HBV-HCC. Conclusion: The interaction between CPAP and HBx can provide a microenvironment to facilitate HCC development via enhancing NF-andkappa;B activation, inflammatory cytokine production, and cancer malignancies. This study not only sheds light on the role of CPAP in HBV-associated HCC, but also provides CPAP as a potential target for blocking the hyper-activated NF-andkappa;B in HCC. andcopy; 2019 The Author(s).

Original languageEnglish
Article number44
JournalJournal of biomedical science
Volume26
Issue number1
DOIs
Publication statusPublished - 2019 Jun 6

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Pharmacology (medical)

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