Abstract
Chronic hepatitis B virus (HBV) infection has been considered as the major cause of hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx) has been reported to be oncogenic. The underlying mechanisms of HBV-related HCC are not fully understood, and the role played by the HBx protein in HBV induced carcinogenesis remains controversial. CDC42, a member of the Rho GTPase family, has been reported to be overexpressed in several different cancers, including HBV-related HCC. However, the specific role of CDC42 in HCC development remains unclear. Here, we investigated the cellular mechanisms by which CDC42 was responsible for the higher proliferation of HuH-7 cells mediated by HBx. We found that the expression level of CDC42 and its activity were significantly increased in HuH-7-HBx cells. The deficiency of CDC42 using the CRISPR/Cas9 system and inhibition by specific inhibitor CASIN led to the reduction of HBx-mediated proliferation. Furthermore, we observed that IQ Motif Containing GTPase Activating Protein 1 (IQGAP1), the downstream mediator of the CDC42 pathway, might be involved in the carcinogenesis induced by HBx. Therefore, the HBx/CDC42/IQGAP1 signaling pathway may potentially play an important role in HBx-mediated carcinogenesis.
Highlights
Hepatocellular carcinoma (HCC) is the fifth common cause of cancer related death worldwide [1]
Our previous quantitative proteomic studies of Hepatitis B virus X protein (HBx) transgenic mice suggested that the Cell division cycle 42 (CDC42) together with its downstream signaling mediators, such as IQ Motif Containing GTPase Activating Protein 1 (IQGAP1), Septin-1, and Cofilin-1 (Figure 1A), play a vital role in HBx induced carcinogenesis of mouse hepatocytes [12]
We found that accompanied with the expression of HBx in HuH-7 cells, the expression of CDC42 was up-regulated at both the mRNA and protein level (Figure 1E)
Summary
Hepatocellular carcinoma (HCC) is the fifth common cause of cancer related death worldwide [1]. Chronic hepatitis B virus (HBV) infection contributes to the great majority of HCC. Compared with the general population, chronic HBV carriers have a 5- to 15-fold increased risk of HCC [2]. Hepatitis B virus X protein (HBx) has been implicated in HBV-related hepatocarcinogenesis and is considered to be oncogenic [3,4]. HBx transgenic mice can develop HCC simultaneously, further demonstrating that HBx may have independent carcinogenic effects [5]. The specific role of HBx in the development of HCC has attracted widespread interest
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