Abstract 1635: MiR-21/Smad 7 signaling determines TGF-β1-induced cancer associated fibroblast (CAF) formation.

Abstract Tumor-secreted growth factors such as TGF-β1 transform adjacent normal fibroblasts into cancer-associated fibroblasts (CAF) which is a major source of CAF. TGF-β1 has canonical and noncanonical Smad pathway, which pathway mediates TGF-β1 signaling during the CAF formation and how TGF-β1 activates regulatory Smad proteins is not entirely understood. To investigate whether the miR-21/Smad 7 signaling determines TGF-β1-induced CAF formation, the in vitro TGF-β1-induced CAF model was successfully established and the function of fibroblasts knocked down or overexpressed miR-21 or Smad 7 were finally identified in the xenografted mice, with or without TGF-β1 stimulation. Our data showed that the mature miR-21 is increased in fibroblast after TGF-β1 treatment, and miR-21 regulates Smad 7 protein level through the translation inhibition instead of the mRNA decay. Moreover, our data showed Smad 3 was phosphorylated 2 hours early than Smad 2 after TGF-β1 stimulation and Smad 7 knockdown enhanced Smad 2 and 3 phosphorylation; both of their phosphorylations were abolished by the TGFR kinase inhibitor. Most important, both of the over-expression of miR-21 or the knockdown of Smad 7 promoted CAF formation, even without TGF-β1 stimulation while the miR-21 knockdown or the Smad 7 overexpression as well as Smad 2, 3 and Smad 4 knock down blocked the TGF-β1-induced CAF formation. These observations suggest that TGF-β1 induces CAF formation through the canonical pathway, miR-21/Smad 7 is a critical mediator. Citation Format: Qiong Li, Yongbin Wang, Wujun Xiong, Jun Mi. MiR-21/Smad 7 signaling determines TGF-β1-induced cancer associated fibroblast (CAF) formation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1635. doi:10.1158/1538-7445.AM2013-1635 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.