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2017 ; 13
(5
): 3646-3652
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Upregulation of maspin expression in human cervical carcinoma cells by
transforming growth factor ?1 through the convergence of Smad and non-Smad
signaling pathways
#MMPMID28521467
Wongnoppavich A
; Dukaew N
; Choonate S
; Chairatvit K
Oncol Lett
2017[May]; 13
(5
): 3646-3652
PMID28521467
show ga
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 ?1 (TGF-?1) 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-?1 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-?1 on maspin upregulation, whereas
pretreatment with pyrrolidine dithiocarbamate (a nuclear factor ?B 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-?1-induced phosphorylation of Smad2. In addition, mutations at
p53-binding sites in the maspin promoter suppressed TGF-?1-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-?1-induced Smad and non-Smad signaling pathways, in which
the latter acts via the intermediate signaling molecules MEK1/2 and p38 MAPK.