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

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-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. Electronic supplementary material The online version of this article (10.1186/s12929-019-0534-9) contains supplementary material, which is available to authorized users.

Gene Signature and Identification of Clinical Trait-Related m6 A Regulators in Pancreatic Cancer

“…Recent studies have found that the m 6 A modification, when the related enzyme is abnormal, plays various roles in a series of human diseases such as neurological disorders, cancer, and embryonic developmental retardation (Wu et al, 2019). Both coding RNAs and some non-coding RNAs, such as lncRNA, microRNA, tRNA, and rRNA and RNA splice body, were regulated by an m 6 A modification before and after transcription (Yen et al, 2019). N6-methyladenosine modification is closely related to the metabolic processes of RNAs, for example, RNA processing, RNA transfer from the nucleus to the cytoplasm, RNA translation, RNA decay, and the biogenesis of RNA (Liang et al, 2020).…”

CPAP enhances and maintains chronic inflammation in hepatocytes to promote hepatocarcinogenesis

“…CPAP was reported to be an essential factor for TNF-α-mediated NF-κB and IL-6-mediated STAT3 activation in HCC [ 29 – 31 ]. Upon HBV infection, the viral oncoprotein HBx transcriptionally increases the expression of CPAP to enhance HCC development [ 30 ]. To evaluate the effects of CPAP in hepatocarcinogenesis, we assessed the physiological roles of overexpressed CPAP in hepatocytes.…”

“…Previous studies reported that HBV-induced chronic liver inflammation is considered a major causative factor of hepatocarcinogenesis [ 4 , 34 ]. CPAP increases HBx protein stability in an NF-κB-dependent manner, and facilitates HCC growth and progression [ 30 ]. To further investigate the ability of overexpressed CPAP in inflammation-induced hepatocarcinogenesis, we generated CH Tg mice.…”

Primary microcephaly with an unstable genome

“…Promote cancer cell proliferation and poorer survival (Bai et al 2019) Up-regulation in gastric cancer cells Promote cell proliferation in cancers by regulating mitotic nuclear division (Song et al 2018) MCPH5/ASPM Overexpression in bladder cancer cells Aggressiveness and poor outcome (Xu et al 2019) Up-regulation in pancreatic ductal adenocarcinoma More aggressiveness and treatment-resistant malignancy (Wang et al 2013a, b) Increased expression in prostate cancer cells Promote tumor cell progression (Pai et al 2019) Overexpression in glioblastoma cells Tumor cell proliferation (Horvath et al 2006) Overexpressed in hepatocellular carcinoma cells Vascular invasion, early recurrence, and poor prognosis (Lin et al 2008) MCPH6/CENPE Overexpressed in HBV-associated hepatocellular carcinoma Promote cancer malignancies (Yen et al 2019) MCPH7/STIL Upregulated in gastric cancer Promote progression and poor overall survival (Wang et al 2019) Upregulated in lung cancer Enhance metastatic spread (Erez et al 2004) Upregulated in colon carcinoma, prostate adenocarcinoma, ovarian cancers Poor prognosis (Erez et al 2004;Wu et al 2019;Rabinowicz et al 2017) Increased expression in pancreatic carcinoma, glioblastoma, kidney carcinoma and cervix adenocarcinoma…”