Ski mediates TGF-beta;1-induced fibrosarcoma cell proliferation and promotes tumor growth

Abstract

Background: TGF-β1 promotes cell proliferation in only some tumors and exerts bidirectional regulatory effects on the proliferation of fibroblasts. This study intends to explore whether the mechanism is related to increased expression of Ski. Methods: Cell proliferation of the fibrosarcoma cell line L929 was assessed with an ELISA BrdU kit. The mRNA and protein expression levels of the corresponding factors were measured by RT-qPCR, immunohistochemistry or Western blotting in vitro and in vivo. Additionally, c-Ski was knocked down using RNAi. The expression of Ski in human dermatofibrosarcoma protuberans (DFSP) specimens was measured by immunohistochemistry. Results: TGF-β1 promoted the continued proliferation of L929 cells in a dose-dependent manner, with increased c-Ski expression levels. Conversely, inhibition of c-Ski significantly abrogated this unidirectional effect, significantly inhibited the decrease in p21 protein levels and did not affect the increase in p-Smad2/3 levels upon TGF-β1 treatment. Similarly, inhibition of c-Ski significantly abrogated the growth-promoting effect of TGF-β1 on xenograft tumors. Furthermore, we found that high expression of Ski in DFSP was correlated with a low degree of tumor differentiation. Conclusions: Our data reveal that high c-Ski expression is a cause of TGF-β1-promoted proliferation in fibrosarcoma tumor cells and show that inhibiting Ski expression might be effective for treating tumors with high Ski levels.