HBV core promoter mutations and AKT upregulate S-phase kinase-associated protein 2 to promote postoperative hepatocellular carcinoma progression.

Lubiao Chen,Hongbo Wang,Yurong Gu,Meihai Deng,Yuehua Huang,Zania Stamataki,Ye Htun Oo,Lin Gu

doi:10.1038/srep35917

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.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common primary malignancies and the third most frequent cause of cancer-related death worldwide[1]
Cell- and animal-based experiments show that AKT1 interacts with several hepatitis B virus (HBV) proteins to contribute to deterioration in liver disease[31]
Some growth regulators have been demonstrated to be good prognostic tools in many other common cancers, the connection between HBV core promoter (CP) mutations and AKT1 has not been carefully investigated by examining the prognostic value of HBV-associated hepatocellular carcinoma (HCC)

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common primary malignancies and the third most frequent cause of cancer-related death worldwide[1]. More than half of all HCC cases occur in China, where almost 100 million people are seropositive for HBV surface antigen (HBsAg)[3,4]. Among those individuals with chronic HBV infection, several viral factors, including the HBV genotypes C, Aa and F; a high viral load; and viral mutations have been reported to be associated with a high risk of HCC5–7. We previously showed that S-phase kinase-associated protein 2 (SKP2), the most critical downstream effector of AKT, is upregulated by mutations in the HBV CP region, which downregulates p21 to accelerate cell cycle progression, anchorage-independent cell growth, and cellular proliferation[22]. SKP2 plays an important role in HBV CP mutation-induced carcinogenesis

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Results

Conclusion