title: Intrahepatic cholangiocarcinoma escapes from growth inhibitory effect of transforming growth factor-beta1 by overexpression of cyclin D1.
abstract: Transforming growth factor-beta1 (TGF-beta1) is involved in tumor progression by promoting angiogenesis or suppressing the immune system; yet TGF-beta1 also has a growth-inhibitory effect on epithelial cells including carcinoma cells. Several mechanisms of impaired TGF-beta1 responsiveness of carcinoma cells have been reported. In this study, we examined how TGF-beta1 participates in the development and progression of intrahepatic cholangiocarcinoma (ICC) associated with hepatolithiasis, and how ICC cells escape from growth inhibitory effect of TGF-beta1. 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-beta1 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 (TbetaR-II) was constantly expressed on biliary epithelial cells irrespective of biliary lesions. In cell culture studies, TGF-beta1 significantly inhibited proliferation of MBEC via downregulation of cyclin D1, cdk4, and cdk6, while TGF-beta1 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-beta1 significantly inhibited the proliferation of ICC cells. In conclusion, high levels of TGF-beta1 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-beta1 by overexpression of cyclin D1.
authors.affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Yoh
authors.initials: Y
authors.lastname: Zen
authors.forename: Kenichi
authors.initials: K
authors.lastname: Harada
authors.forename: Motoko
authors.initials: M
authors.lastname: Sasaki
authors.forename: Tse-Ching
authors.initials: TC
authors.lastname: Chen
authors.forename: Miin-Fu
authors.initials: MF
authors.lastname: Chen
authors.forename: Ta-Sen
authors.initials: TS
authors.lastname: Yeh
authors.forename: Yi-Yin
authors.initials: YY
authors.lastname: Jan
authors.forename: Shiu-Feng
authors.initials: SF
authors.lastname: Huang
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nimura
authors.forename: Yasuni
authors.initials: Y
authors.lastname: Nakanuma
mesh_terms: D002455:Cell Division / Q000502:physiology*; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D016212:Transforming Growth Factor beta