Upregulation of maspin expression in human cervical carcinoma cells by transforming growth factor β1 through the convergence of Smad and non-Smad signaling pathways
نویسندگان
چکیده
Mammary serine protease inhibitor (maspin), encoded by the serpin family B member 5 gene, serves as a tumor suppressor through the inhibition of cancer cell invasion and metastasis. Paradoxically, maspin levels are upregulated in a number of types of malignant cells. Therefore, the regulation of maspin expression may depend on the genetic or epigenetic background and the specific microenvironment of carcinoma cells. In the present study, it was demonstrated that transforming growth factor β1 (TGF-β1) induced maspin expression at the transcript and protein levels in the human cervical carcinoma HeLa and human oral squamous carcinoma HSC4 cell lines. The inhibition of the mothers against decapentaplegic homolog (Smad)-dependent pathway by a Smad3-specific inhibitor suppressed maspin induction by TGF-β1 in HeLa cells. Inhibition of the non-Smad pathway by pretreatment with the mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor U0126, or the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB202190, attenuated the effect of TGF-β1 on maspin upregulation, whereas pretreatment with pyrrolidine dithiocarbamate (a nuclear factor κB inhibitor), wortmannin (a phosphoinositide 3-kinase inhibitor) or SP600125 (a c-Jun N-terminal kinase inhibitor) did not. Notably, none of these inhibitors eliminated the TGF-β1-induced phosphorylation of Smad2. In addition, mutations at p53-binding sites in the maspin promoter suppressed TGF-β1-induced maspin expression, indicating the necessity of intact p53-binding sites on the maspin promoter. In summary, the induction of maspin expression in HeLa cells requires the convergence of TGF-β1-induced Smad and non-Smad signaling pathways, in which the latter acts via the intermediate signaling molecules MEK1/2 and p38 MAPK.
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عنوان ژورنال:
دوره 13 شماره
صفحات -
تاریخ انتشار 2017