title: HBV core promoter mutations and AKT upregulate S-phase kinase-associated protein 2 to promote postoperative hepatocellular carcinoma progression.
abstract: Mutations in the hepatitis B virus (HBV) core promoter (CP) have been shown to be associated with hepatocellular carcinoma (HCC). The CP region overlaps HBV X gene, which activates AKT to regulate hepatocyte survival. However, the cooperation between these two cascades in HCC progression remains poorly understood. Here, we assayed virological factors and AKT expression in liver tissues from 56 HCC patients with better prognoses (BHCC, ≥5-year survival) and 58 with poor prognoses (PHCC, <5-year survival) after partial liver resection. Results showed double mutation A1762T/G1764A (TA) combined with other mutation(s) (TACO) in HBV genome and phosphorylated AKT (pAKT) were more common in PHCC than BHCC. TACO and pAKT levels correlated with proliferation and microvascularization but inversely correlated with apoptosis in HCC samples. These were more pronounced when TACO and pAKT co-expressed. Levels of p21 and p27 were decreased in TACO or pAKT overexpressing HCC due to SKP2 upregulation. Levels of E2F1 and both mRNA and protein of SKP2 were increased in TACO expressing HCC. Levels of 4EBP1/2 decreased and SKP2 mRNA level remained constant in pAKT-overexpressing HCC. Therefore, TACO and AKT are two independent predictors of postoperative survival in HCC. Their co-target, SKP2 may be a diagnostic or therapeutic marker.
authors: Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors: Lubiao
authors: L
authors: Chen
authors: Guangdong Provincial Key Laboratory of Liver Diseases Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors: Lin
authors: L
authors: Gu
authors: Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors: Yurong
authors: Y
authors: Gu
authors: Guangdong Provincial Key Laboratory of Liver Diseases Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors: Hongbo
authors: H
authors: Wang
authors: Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors: Meihai
authors: M
authors: Deng
authors: Institute of Biomedical Research and NIHR Center for Liver Disease, University of Birmingham, Birmingham, United Kingdom.
authors: Zania
authors: Z
authors: Stamataki
authors: Institute of Biomedical Research and NIHR Center for Liver Disease, University of Birmingham, Birmingham, United Kingdom.
authors: Ye Htun
authors: YH
authors: Oo
authors: Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.|Guangdong Provincial Key Laboratory of Liver Diseases Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors: Yuehua
authors: Y
authors: Huang
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000473:pathology* / Q000821:virology*; D018450:Disease Progression; D005786:Gene Expression Regulation; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000473:pathology / Q000821:virology; D009154:Mutation; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*
chemical_list: D044786:S-Phase Kinase-Associated Proteins; D051058:Oncogene Protein v-akt