Urocortin Attenuates TGFβ1‐Induced Snail1 and Slug Expressions: Inhibitory Role of Smad7 in Smad2/3 Signaling in Breast Cancer Cells

Abstract

Corticortropin-releasing hormone (CRH) family are multifunctional endocrine-factors that regulate proliferation, apoptosis, and migration of various types of cancer cells. Deregulation of the transforming growth factor β1(TGFβ1) signal transduction promotes aggressive metastatic properties in late-stage breast cancers. We previously have demonstrated in breast cancer cell line that CRH suppressed TGFβ1-induced Epithelial-Mesenchymal Transition (EMT) via induction of E-cadherin. Our present data in MCF-7 and MDA-MB-231 cells showed that Urocortin (Ucn, a member of CRH family) inhibited TGFβ1 signaling by reducing Smad2/3 activation and subsequent nuclear translocation through increasing Smad7 expression, leading to downregulation of Snail1 and Slug, the two EMT promoters. We further found that Antalarmin (CRH receptor type 1, CRHR1 antagonist) and Antisauvagine-30 (CRH receptor type2, CRHR2 antagonist) abrogated the effects of Ucn on TGFβ1 signaling, implying that both active CRHR1 and CRHR2 participate in Ucn-repressed TGFβ1 signaling. Our findings, for the fist time, identify Ucn as a potential mediator that inhibits oncogenic signaling by TGFβ1 and suggest that activating CRHR1 and R2 may prove effective in diminishing breast cancer progression stimulated by TGFβ1.

SMAD‑6, ‑7 and ‑9 are potential molecular biomarkers for the prognosis in human lung cancer

“…Moreover, it was found that SMAD7 is markedly correlated with SMAD-2 as shown in Fig. 5B, which is also consistent with the finding that the expression of SMAD-2 is regulated by inhibitory SMAD-7 activity in a negative feedback in cancer cells (73).…”

RAC1B Induces SMAD7 via USP26 to Suppress TGFβ1-Dependent Cell Migration in Mesenchymal-Subtype Carcinoma Cells

“…This clearly indicates that SMAD7 can mimic the effect of RAC1B on transcriptional induction of individual genes involved in EMT and cell invasion. In good match with our results, siRNA-mediated knockdown of SMAD7 increased TGFβ-induced activation of SMAD3 in MDA-MB-231 cells [ 31 ]. In sum, these data show that SMAD7 mimics the inhibitory effect of RAC1B on ALK5 protein expression and provide further evidence for the assumption that RAC1B exerts its inhibitory effect on TGFβ/Smad-mediated gene expression at least in part through upregulation of SMAD7.…”

The critical role of EGF-β-catenin signaling in the epithelial-mesenchymal transition in human glioblastoma

“…Increasing reports indicate that a complex cross-talk exists between the β-catenin pathway and other signaling molecules, and EMT-corresponding effectors 22–24. In the present study, we identified the in vitro effect of β-catenin on different malignant phenotypes in U87 glioblastoma cells.…”