Dichlorodiphenyltrichloroethane exposure induces the growth of hepatocellular carcinoma via Wnt/β-catenin pathway

Dichlorodiphenyltrichloroethane (DDT) is a persistent organic pollutant, involved in the progression of many cancers, including liver cancer. However, the underlying mechanism(s) of DDT, especially how low doses DDT cause liver cancer, is poorly understood. In this study, we evaluated the impact of p,p'-DDT on the growth of hepatocellular carcinoma using both in vitro and in vivo models. The present data indicated that the proliferation of HepG2 cells was strikingly promoted after exposed to p,p'-DDT for 4 days. In addition, reactive oxygen species (ROS) content was significantly elevated, accompanied with inhibitions of gamma-glutamylcysteine synthetase (gamma-GCS) and superoxide dismutase (SOD) activities. Interestingly, the levels of beta-catenin and its downstream target genes (c-Myc and CyclinD1) were significantly up-regulated, and co-treatment of NAC, the ROS inhibitor, inhibited these over-expressed proteins. Moreover, the p,p'-DDT-stimulated proliferation of HepG2 cells could be reversed after NAC or beta-catenin siRNA co-treatment. Likewise, p,p'-DDT treatment increased the growth of tumor in nude mice, stimulated oxidative stress and Wnt/beta-catenin pathway. Our study indicates that low doses p,p'-DDT exposure promote the growth of hepatocellular carcinoma via Wnt/beta-catenin pathway which is activated by oxidative stress. The finding suggests an association between low dose DDT exposure and liver cancer growth. Crown Copyright (C) 2013 Published by Elsevier Ireland Ltd. All rights reserved.