Hepatitis B virus X protein upregulates oncogene Rab18 to result in the dysregulation of lipogenesis and proliferation of hepatoma cells

Abstract

Hepatitis B virus X protein (HBx) contributes to the development of hepatocellular carcinoma (HCC) through inducing dysregulation of lipogenesis. However, the mechanism by which HBx induces the abnormal lipogenesis is not well known. In this study, we report that the oncogene Rab18, a member of Ras family, enhances the HBx-induced hepatocarcinogenesis through inducing dysregulation of lipogenesis and proliferation. Our data showed that the expression levels of Rab18 were positively associated with those of HBx in clinical HCC tissues. HBx was able to upregulate the expression of Rab18 in p21-HBx transgenic mice and hepatoma cell lines. Next, we identified the mechanism by which HBx upregulated Rab18. The results demonstrated that cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) were able to stimulate Rab18 promoter through activating transcription factor activator protein 1 (AP-1) and cyclic adenosine 3',5'-monophosphate response element-binding (CREB). In addition, we identified another pathway that HBx activated Rab18. We found that miR-429 was able to directly target the 3' untranslated region of Rab18, suggesting that Rab18 is one of the target genes of miR-429. Then, we found that HBx was able to downregulate miR-429 in hepatoma cells. The oil red O staining showed that HBx resulted in the dysregulation of lipogenesis through Rab18. Moreover, Rab18 contributed to the HBx-enhanced proliferation of hepatoma cells in vitro and in vivo. HBx enhances hepatocarcinogenesis through leading to the dysregulation of lipogenesis and proliferation of hepatoma cells, involving two pathways such as HBx/COX-2/5-LOX/AP-1/CREB/Rab18 and HBx/miR-429/Rab18.

The Kaposi's Sarcoma-Associated Herpesvirus (KSHV)-Induced 5-Lipoxygenase-Leukotriene B4 Cascade Plays Key Roles in KSHV Latency, Monocyte Recruitment, and Lipogenesis

“…5LO is an emerging target in obesity, insulin resistance, obesity-related fatty liver disease, metabolic dysfunction (118,119), and nonalcoholic fatty liver and nonalcoholic steatohepatitis (120). Since 5LO/LTB4 has been shown to induce lipogenesis in human sebocytes (121), breast cancer cells (60), and hepatitis B virus X protein-mediated development of hepatocellular carcinoma (122) and since 5LO inhibitors are known to directly downregulate lipogenesis in sebocytes (121) and hepatic steatosis (119), we hypothesized that KSHV infection induces the 5LO/LTB4 cascade to enhance lipogenesis (123,124) and favor latency. Our results show that LTB4 promotes FASN transcription and gene expression and silencing of 5LO effectively reduces the protein levels of FASN (Fig.…”

MiR-506 suppresses proliferation of hepatoma cells through targeting YAP mRNA 3′UTR

“…As a heterogeneous tumor, HCC develops through the activation of multiple pathways and molecular alterations [24,25] . The development and progression of HCC is a complicated process that involves the deregulation of multiple genes that are essential to cellular biological processes.…”

Control of oxidative stress in hepatocellular carcinoma: Helpful or harmful?

“…HBx protein regulates some oncogenes and affects several apoptosisrelated signaling pathways [36] . Through binding to transcription factors such as CREB, RPB5, TFIIB, XAP-1, C/EBPalpha and XAP3, HBx can upregulate oncogenes such as Rab18 or Yesassociated protein [38,39] . HBx induces apoptosis by upregulating FasL protein through activating MLK3/MKK7/JNKs signaling and interacting with Bcl-2/CED-9 signaling [40,41] .…”