Ski mediates TGF-β1-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.

Insights into Gene Regulation under Temozolomide-Promoted Cellular Dormancy and Its Connection to Stemness in Human Glioblastoma

“…As mentioned above and in accordance with the correlations of SKI with CCRL1 and SLFN13 found in our study, SKI was mainly postulated to exert tumor-promoting effects [13][14][15]. Various mechanisms were identified to investigate its function as an influence on Wnt/beta-catenin, phosphatidylinositol 3-kinase/protein kinase B and transforming growth factor (TGF)-ß signaling pathway [40][41][42]. Despite Chen et al also postulating a tumor-suppressive function in lung cancer [12], in GBM, SKI was shown to negatively regulate the TGF-β signaling pathway, leading to the promotion of tumor progression [43].…”

“…Here, enhanced SKI expression increased the expression of the pluripotency maintaining markers such as Sox2 and OCT4, and also components of the sonic-hedgehog pathway (Shh), indicating that SKI might be an important factor in maintaining the stemness of pancreatic cancer stem cells through modulating the Shh pathway [60]. Since SKI is involved in the TGF-ß signaling pathway as previously mentioned [42], which in turn is known to support self-renewal of glioma-initiating stem cells [61], the TGF-ß/SKI pathway appears to be of particular importance in GSCs. Indeed, when inhibiting SKI by Disitertide (P144) in our in vitro model of TMZ-promoted dormancy entry and exit, higher cytotoxicity, a stronger inhibition of GBM cell proliferation, and a reduced neurosphere formation capacity along with lower expression of stemness markers were observed.…”

Lentivirus-mediated knockdown of Ski inhibits glial scar formation and promotes axonal regeneration and functional recovery after spinal cord injury in rats

“…Since its rst discovery as an oncogene in 1986, the Ski gene has been widely recognized as an oncogenic regulator of a variety of malignancies, mediating cancer cell proliferation, differentiation, metastasis and invasion through a variety of mechanisms [28]. In the course of subsequent studies, researchers also found that Ski plays a key role in regulating the activation and proliferation of broblasts as well as broma cells [50][51][52]. In a previous study by our group, we found that Ski was signi cantly upregulated in rat spinal cord and activated astrocytes after spinal cord injury [32].…”

S100A2 induces epithelial–mesenchymal transition and metastasis in pancreatic cancer by coordinating transforming growth factor β signaling in SMAD4-dependent manner

“…Canonical TGF-β signaling is correlated with the activation of serine/threonine kinase receptors, thereby facilitating the phosphorylation of receptor-regulated SMADs (R-Smads; SMAD2 and SMAD3). R-Smads and SMAD4 can generate heteromeric complexes, which exhibit nuclear translocation and accumulation [ 12 , 13 ]. Moreover, R-Smads can modulate the levels of target genes along with cofactors or sequence-specific transcription factors [ 14 ].…”