Hepatitis C virus core protein interacts with Snail and histone deacetylases to promote the metastasis of hepatocellular carcinoma

Abstract

Downregulation of E-cadherin by the transcriptional repressor Snail is associated with acquisition of metastatic potential. Although hepatitis C virus (HCV) core protein has been implicated in hepatocarcinogenesis, it is unclear whether Snail is involved in HCV core-induced dysregulation of E-cadherin. Herein, we investigated the mechanism by which HCV core induces E-cadherin repression and the role of Snail in HCV core-mediated invasiveness and metastasis. We found that HCV infection, especially HCV core expression, effectively induced the epithelial-mesenchymal transition (EMT) in hepatoma cells by repressing E-cadherin. HCV core interacted with Snail and enhanced its binding to the E-box in the promoter region of E-cadherin, leading to decreased E-cadherin promoter activity. We found that HCV core, Snail, and the histone deacetylases HDAC1/HDAC2 formed a co-repressor complex at the E-cadherin promoter. Moreover, HCV core was shown to stabilize Snail through activation of the PI3K/Akt/GSK3β pathway. Silencing Snail expression restored E-cadherin expression and inhibited HCV core-promoted tumor growth and distant lung metastasis in vivo. Collectively, these results demonstrated that HCV core induced EMT by interacting with the transcriptional repressor complex Snail/HDACs at the E-cadherin promoter, which led to E-cadherin repression and increased invasiveness of hepatoma cells. These findings increase understanding of factors regulating metastasis in hepatoma and may ultimately lead to the development of novel treatment strategies for HCV-associated hepatocellular carcinoma.

High expression of Snail and NF-κB predicts poor survival in Chinese hepatocellular carcinoma patients

“…We found that both Snail and NF-κB were expressed in HCC tissues and that their expression levels were good predictors of the degree of tumor differentiation and of patient survival. Our observation that nearly all HCC patients are positive for both Snail and NF-κB is consistent with earlier studies [8, 13, 14–16]. Previous in vitro studies also showed that activation of NF-κB signaling increases Snail expression [6, 12, 13, 17], which is consistent with our finding that levels of Snail expression correlate closely with those of NF-κB expression in human HCC samples.…”

Hepatitis C virus core protein increases Snail expression and induces epithelial–mesenchymal transition through the signal transducer and activator of transcription 3 pathway in hepatoma cells

“…Interestingly, a recent study showed that HCV core interacted with Snail and enhanced its binding to the E-cadherin promoter, and HCV core stabilized Snail through the PI3K/Akt/GSK3β pathway, indicating different molecular mechanisms would be involved in the regulation of Snail and EMT in HCV-related HCC. 29 Altogether, these findings provide new insights into the mechanism of HCVmediated invasiveness and metastasis in HCC, and highlight Snail as an attractive molecular target for preventing/treating HCV-related HCC.…”

Chromatin remodeling geneARID2targets cyclin D1 and cyclin E1 to suppress hepatoma cell progression

“…The adenoviral recombinant pAd-ARID2 was also generated using the AdEasy system [30]. An analogous adenovirus expressing only GFP (Ad-GFP) and a scrambled shRNA (AdR-siControl) expressing RFP were used as controls.…”