Intrahepatic cholangiocarcinoma escapes from growth inhibitory effect of transforming growth factor-beta1 by overexpression of cyclin D1.
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.
Zen
Yoh
Y
Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
Harada
Kenichi
K
Sasaki
Motoko
M
Chen
Tse-Ching
TC
Chen
Miin-Fu
MF
Yeh
Ta-Sen
TS
Jan
Yi-Yin
YY
Huang
Shiu-Feng
SF
Nimura
Yuji
Y
Nakanuma
Yasuni
Y
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*
D016212:Transforming Growth Factor beta