Cx32 reverses epithelial-mesenchymal transition in doxorubicin-resistant hepatocellular carcinoma.

Recently, epithelial-mesenchymal transition (EMT) has been reported to be an important mechanism of drug resistance in numerous types of cancer cells, including hepatocellular carcinoma (HCC). However, the underlying mechanisms remain to be fully elucidated. Connexin (Cx)32 plays a crucial role in hepatocarcinogenesis. The present study investigated the role of Cx32 in the regulation of chemotherapy-induced EMT in HCC. We found that the expression levels of Cx32 and E-cadherin were clearly decreased in HCC tissues compared with the corresponding paracancerous tissues, while the expression level of vimentin was significantly enhanced in HCC tissues. The expression of Cx32 had a strong correlation with the expression of E-cadherin and vimentin. In an in vitro study, a doxorubicin (DOX)-resistant liver cell line HepG2/DOX was established from parental HepG2 cells. The results showed that HepG2/DOX cells acquired EMT characteristics, with a decreased expression level of E-cadherin and an enhanced expression level of vimentin, and possessed high migratory abilities and invasiveness. Meanwhile, Cx32 was significantly decreased in the HepG2/DOX cells. Knockdown of Cx32 by shRNA in HepG2 cells induced EMT, while overexpression of Cx32 converted EMT to mesenchymal-epithelial transition (MET) in the HepG2/DOX cells. These results suggest that Cx32 is an important regulator of DOX-induced EMT in HCC. Cx32 could be considered as a novel target to reverse DOX resistance in HCC.