Xu Yongru, Qi Yingzi, Luo Jing, Yang Jing, Xie Qi, Deng Chen, Su Na, Wei Wei, Shi Deshun, Xu Feng, Li Xiangping, Xu Ping
State Key Laboratory of Proteomics, Beijing Proteome Research Centre, National Engineering Research Centre for Protein Drugs, National Centre for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing 102206, China.
State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning 530005, China.
Int J Mol Sci. 2017 Mar 8;18(3):586. doi: 10.3390/ijms18030586.
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.
慢性乙型肝炎病毒（HBV）感染一直被认为是肝细胞癌（HCC）的主要病因。据报道，乙型肝炎病毒X蛋白（HBx）具有致癌性。HBV相关HCC的潜在机制尚未完全阐明，且HBx蛋白在HBV诱导的致癌过程中所起的作用仍存在争议。CDC42是Rho GTPase家族的成员之一，据报道在包括HBV相关HCC在内的几种不同癌症中均有过表达。然而，CDC42在HCC发展中的具体作用仍不清楚。在此，我们研究了CDC42导致HBx介导的HuH-7细胞增殖增加的细胞机制。我们发现，在HuH-7-HBx细胞中，CDC42的表达水平及其活性显著增加。使用CRISPR/Cas9系统敲除CDC42以及用特异性抑制剂CASIN抑制CDC42，均导致HBx介导的增殖减少。此外，我们观察到，CDC42信号通路的下游介质含IQ基序的GTP酶激活蛋白1（IQGAP1）可能参与了HBx诱导的致癌过程。因此，HBx/CDC42/IQGAP1信号通路可能在HBx介导的致癌过程中发挥重要作用。
