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

Abstract

Transforming growth factor-b1 (TGF-b1) is involved in tumor progression by promoting angiogenesis or suppressing the immune system; yet TGF-b1 also has a growth-inhibitory effect on epithelial cells including carcinoma cells. Several mechanisms of impaired TGF-b1 responsiveness of carcinoma cells have been reported. In this study, we examined how TGF-b1 participates in the development and progression of intrahepatic cholangiocarcinoma (ICC) associated with hepatolithiasis, and how ICC cells escape from growth inhibitory effect of TGF-b1. 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-b1 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-b type II receptor (TbR-II) was constantly expressed on biliary epithelial cells irrespective of biliary lesions. In cell culture studies, TGF-b1 significantly inhibited proliferation of MBEC via downregulation of cyclin D1, cdk4, and cdk6, while TGF-b1 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-b1 significantly inhibited the proliferation of ICC cells. In conclusion, high levels of TGF-b1 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-b1 by overexpression of cyclin D1.

Identification of Cellular Targets in Human Intrahepatic Cholangiocarcinoma Using Laser Microdissection and Accurate Mass and Time Tag Proteomics

“…The expression of TGF␤, a potent inducer of EMT (79), is increased in many human cancers (80) including ICC (81,82). Interestingly, the protein alterations found in tumorous cholangiocytes (present study) displayed striking similarities with those reported in the A549 human lung adenocarcinoma cell line (83) during TGF␤-induced EMT.…”

Expression of transforming growth factor β1 promotes cholangiocarcinoma development and progression

“…In this study, targeting TGFβ1 both with specific shRNA and pharmacological compounds substantially inhibited CCA growth; the underlying mechanisms for TGFβ1 effects were explored. Previous findings indicate that TGFβ1 promotes p21 but suppresses cyclin D1 expression[36, 38], likewise, we also observed that inhibition of TGFβ1 promotes p21 but inhibits cyclin D1 expression. In addition, miR-34a was found to be important in shTGFβ1-mediated CCA tumor progression.…”

“…However, there is controversy regarding the role of TGFβ1 on CCA growth and progression [36, 37]. Most studies on TGFβ1 signaling in CCA are related to short-term exposure with recombinant TGFβ1 protein and it is not apparent if these effects continue to be active under long-term in vivo conditions associated with tumor progression.…”

Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor-β1/Snail Activation Aggravates Invasive Growth of Cholangiocarcinoma

“…28 However, our previous studies showed that TGF-␤1 did not influence the proliferation of CCKS-1, and we identified that overexpression of cyclin D1 was an underlying causative mechanism of this phenomenon. 29 Although the effects of TGF-␤1 on apoptosis remain to be determined in cholangiocarcinoma, no influence on the cellular proliferative activity of CCKS-1 by TGF-␤1 implies that TGF-␤1 may not have apoptosis-inducing capacity. Therefore, the blockage of TGF-␤ signaling pathways may be able to reduce the activity of invasive potential of Figure 7.…”