Intrahepatic cholangiocarcinoma escapes from growth inhibitory effect of transforming growth factor-β1 by overexpression of cyclin D1

Abstract

Transforming growth factor-β1 (TGF-β1) is involved in tumor progression by promoting angiogenesis or suppressing the immune system; yet TGF-β1 also has a growth-inhibitory effect on epithelial cells including carcinoma cells. Several mechanisms of impaired TGF-β1 responsiveness of carcinoma cells have been reported. In this study, we examined how TGF-β1 participates in the development and progression of intrahepatic cholangiocarcinoma (ICC) associated with hepatolithiasis, and how ICC cells escape from growth inhibitory effect of TGF-β1. A total of 40 cases of hepatolithiasis were studied, including 16 cases of ICC, and in vitro studies were conducted with cultured murine non-neoplastic biliary epithelial cells (MBEC) and three ICC cell lines. Immunohistochemically, TGF-β1 was expressed in mononuclear cells and mesenchymal cells around the stone-containing bile ducts and invasive ICC, and also in biliary epithelial cells (hyperplastic and precursor lesions, and ICC). TGF-β type II receptor (TβR-II) was constantly expressed on biliary epithelial cells irrespective of biliary lesions. In cell culture studies, TGF-β1 significantly inhibited proliferation of MBEC via downregulation of cyclin D1, cdk4, and cdk6, while TGF-β1 did not influence the proliferation of ICC cells. After suppression of cyclin D1 expression in one ICC cell line using cyclin D1 small interfering RNA, TGF-β1 significantly inhibited the proliferation of ICC cells. In conclusion, high levels of TGF-β1 around ICC or its precursors may be involved in development and progression of ICC in hepatolithiasis. ICC cells could escape the growth inhibitory effect of TGF-β1 by overexpression of cyclin D1.