RRC ID 60106
Author Taguchi L, Miyakuni K, Morishita Y, Morikawa T, Fukayama M, Miyazono K, Ehata S.
Title c-Ski accelerates renal cancer progression by attenuating transforming growth factor β signaling.
Journal Cancer Sci
Abstract Although transforming growth factor beta (TGF-β) is known to be involved in the pathogenesis and progression of many cancers, its role in renal cancer has not been fully investigated. In the present study, we examined the role of TGF-β in clear cell renal carcinoma (ccRCC) progression in vitro and in vivo. First, expression levels of TGF-β signaling pathway components were examined. Microarray and immunohistochemical analyses showed that the expression of c-Ski, a transcriptional corepressor of Smad-dependent TGF-β and bone morphogenetic protein (BMP) signaling, was higher in ccRCC tissues than in normal renal tissues. Next, a functional analysis of c-Ski effects was carried out. Bioluminescence imaging of renal orthotopic tumor models demonstrated that overexpression of c-Ski in human ccRCC cells promoted in vivo tumor formation. Enhancement of tumor formation was also reproduced by the introduction of a dominant-negative mutant TGF-β type II receptor into ccRCC cells. In contrast, introduction of the BMP signaling inhibitor Noggin failed to accelerate tumor formation, suggesting that the tumor-promoting effect of c-Ski depends on the inhibition of TGF-β signaling rather than of BMP signaling. Finally, the molecular mechanism of the tumor-suppressive role of TGF-β was assessed. Although TGF-β signaling did not affect tumor angiogenesis, apoptosis of ccRCC cells was induced by TGF-β. Taken together, these findings suggest that c-Ski suppresses TGF-β signaling in ccRCC cells, which, in turn, attenuates the tumor-suppressive effect of TGF-β.
Volume 110(6)
Pages 2063-2074
Published 2019-6
DOI 10.1111/cas.14018
PMID 30972853
PMC PMC6550129
MeSH Adult Aged Aged, 80 and over Animals Carcinoma, Renal Cell / genetics* Carcinoma, Renal Cell / metabolism Carcinoma, Renal Cell / pathology Cell Line, Tumor DNA-Binding Proteins / genetics* DNA-Binding Proteins / metabolism Disease Progression Female Gene Expression Profiling / methods Humans Kidney Neoplasms / genetics* Kidney Neoplasms / metabolism Kidney Neoplasms / pathology Male Mice, Inbred BALB C Mice, Nude Middle Aged Proto-Oncogene Proteins / genetics* Proto-Oncogene Proteins / metabolism Signal Transduction / genetics* Transforming Growth Factor beta / genetics* Transforming Growth Factor beta / metabolism Transplantation, Heterologous
IF 4.751
Times Cited 2
Human and Animal Cells OS-RC-2(RCB0735)