The evaluation of p,p′-DDT exposure on cell adhesion of hepatocellular carcinoma

•Low doses p,p′-DDT exposure disrupts cell–cell adhesion and cell–matrix adhesion in HepG2 cells.•Both oxidative stress and JAK/STAT3 pathway are activated in p,p′-DDT-treated HepG2 cells.•The stimulation of JAK/STAT3 pathway is mediated by oxidative stress.•p,p′-DDT regulates adhesion molecules via the JAK/STAT3 pathway.•p,p′-DDT stimulates JAK/STAT3 signal pathway and disrupts the expressions of cell adhesion molecules in nude mice models.

Many studies have found a positive association between the progression of hepatocellular carcinoma and DDT exposure. These studies mainly focus on the effect of DDT exposure on cell proliferation and epithelial to mesenchymal transition (EMT) promotion. However, the influence of DDT on cell adhesion of hepatocellular carcinoma remains to be unclear. The aim of our study was to determine the effect of p,p′-DDT on cell adhesion of hepatocellular carcinoma in vitro and in vivo. The data showed that p,p′-DDT, exposing HepG2 cells for 6 days, decreased cell–cell adhesion and elevated cell–matrix adhesion. Strikingly, p,p′-DDT increased reactive oxygen species (ROS) content, and this was accompanied by the activation of JAK/STAT3 pathway. Moreover, ROS inhibitor supplement reversed these effects significantly. However, the addition of ER inhibitor, ICI, had no effect on the p,p′-DDT-induced effects. p,p′-DDT altered the mRNA levels of related adhesion molecules, including inhibition of E-cadherin and promotion of N-cadherin along with CD29. Interestingly, the p,p′-DDT-altered adhesion molecules could be reversed with JAK inhibitor or STAT3 inhibitor. Likewise, p,p′-DDT stimulated the JAK/STAT3 pathway in nude mice, as well as altered the mRNA levels of E-cadherin, N-cadherin, and CD29. Taken together, these results indicate that p,p′-DDT profoundly promotes the adhesion process by decreasing cell–cell adhesion and inducing cell–matrix adhesion via the ROS-mediated JAK/STAT3 pathway. All these events account for the carcinogenic potential of p,p′-DDT in liver.

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