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

Transforming growth factor-beta 1 (TGF-beta 1) is involved in tumor progression by promoting angiogenesis or suppressing the immune system; yet TGF-beta 1 also has a growth-inhibitory effect on epithelial cells including carcinoma cells. Several mechanisms of impaired TGF-beta 1 responsiveness of carcinoma cells have been reported. In this study, we examined how TGF-beta 1 participates in the development and progression of intrahepatic cholangiocarcinoma (ICC) associated with hepatolithiasis, and how ICC cells escape from growth inhibitory effect of TGF-beta 1. 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-beta 1 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-beta type II receptor (T beta R-II) was constantly expressed on biliary epithelial cells irrespective of biliary lesions. In cell culture studies, TGF-beta 1 significantly inhibited proliferation of MBEC via downregulation of cyclin D1, cdk4, and cdk6, while TGF-beta 1 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-beta 1 significantly inhibited the proliferation of ICC cells. In conclusion, high levels of TGF-beta 1 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-beta 1 by overexpression of cyclin D1.