Trefoil Factor Family 1 Inhibits the Development of Hepatocellular Carcinoma by Regulating β-Catenin Activation.

Abstract

Recent studies have suggested that trefoil factor family 1 (TFF1) functions as a tumor suppressor in gastric and pancreatic carcinogenesis. To investigate the role of TFF1 in hepatocarcinogenesis, we performed immunohistochemical staining of surgically resected human liver samples, transfected a TFF1 expression vector into hepatocellular carcinoma (HCC) cell lines, and employed a mouse model of spontaneous HCC development (albumin-cyclization recombination/Lox-Stop-Lox sequence-Kirsten rat sarcoma viral oncogene homologG12D [KC]); the model mouse strain was bred with a TFF1-knockout mouse strain to generate a TFF1-deficient HCC mouse model (KC/TFF1-/- ). TFF1 expression was found in some human samples with HCC. Interestingly, TFF1-positive cancer cells showed a staining pattern contradictory to that of proliferating cell nuclear antigen, and aberrant DNA hypermethylation in TFF1 promoter lesions was detected in HCC samples, indicating the tumor-suppressive role of TFF1. In vitro, induction of TFF1 expression resulted in impaired proliferative activity and enhanced apoptosis in HCC cell lines (HuH7, HepG2, and HLE). These anticancer effects of TFF1 were accompanied by the loss of nuclear β-catenin expression, indicating inactivation of the β-catenin signaling pathway by TFF1. In vivo, TFF1 deficiency in KC mice accelerated the early development and growth of HCC, resulting in poor survival rates. In addition, immunohistochemistry revealed that the amount of nuclear-localized β-catenin was significantly higher in KC/TFF1-/- mice than in KC mice and that human HCC tissue showed contradictory expression patterns for β-catenin and TFF1, confirming the in vitro observations. TFF1 might function as a tumor suppressor that inhibits the development of HCC by regulating β-catenin activity.