Regulation of ABCG2 expression by Wnt5a through FZD7 in human pancreatic cancer cells

ATP-binding cassette subfamily G member 2 (ABCG2), a member of the ABC transporter superfamily, has been implicated in the development of chemotherapeutic drug resistance in cancer cells. However, the regulators of ABCG2 expression and their roles in anticancer drug resistance have not been fully characterized, especially in the context of pancreatic cancer. The aim of the present study was to investigate whether ABCG2 contributed to drug resistance in pancreatic cancer and to elucidate its regulatory molecular pathways. Using immunohistochemical analysis of pancreatic ductal adenocarcinoma and adjacent healthy tissue samples, the present study identified a positive correlation between ABCG2 and Wnt5a, a member of the Wnt family of secreted proteins. It was also determined that treatment with recombinant human Wnt5a protein could upregulate the expression of ABCG2 in the Capan-2 human pancreatic cancer cell line and enhance its resistance to gemcitabine. The upregulation of ABCG2 by Wnt5a was inhibited by small interfering RNA silencing of Frizzled class receptor 7 (FZD7) or by FZD7 inhibitors. Moreover, both FZD7 silencing or inhibition of its function attenuated gemcitabine resistance induced by Wnt5a in Capan-2 cells. Therefore, the present findings suggested that Wnt5a and FZD7 acted as upstream regulators of ABCG2 expression and that FZD7 may be an essential factor for Wnt5a-induced gemcitabine resistance in pancreatic cancer cells.