• 作者： 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 and Liang-Yi Hung
• 作者服務機構： 1. Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan 2. Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan 3. Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan 4. Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan 5. Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan 6. Department of Pharmacology, National Cheng Kung University, Tainan, 70101, Taiwan 7. Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, 70101, Taiwan
• 中文摘要：
• 英文摘要：
  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-κB) 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-κB 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-2′-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-κB-dependent manner; and the expression levels of CPAP and HBx were positively correlated with the activation status of NF-κB 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-κB 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-κB in HCC.
• 中文關鍵字：
• 英文關鍵字： Hepatocarcinogenesis, CPAP, HBx, NF-κB, Inflammation