Requirement of TGFbeta signaling for SMO-mediated carcinogenesis.

ABSTRACT: Hedgehog (Hh) signaling, via the key signal transducer Smoothened (SMO) and Gli transcription factors, is essential for embryonic development and carcinogenesis. At present, the molecular mechanism of Hh signaling-mediated carcinogenesis is not completely understood. Using a mouse model (K14cre/R26SmoM2) of SMO-mediated basal cell carcinoma development, we identified TGF?2 as a major Hh-regulated gene. TGF?2 expression was high in the keratinocytes, with activated TGF? signaling (indicated by elevated expression of phosphorylated SMAD2/3) detected in both tumor and stroma. The significance of TGF? signaling for SMO function was demonstrated in two assays. Down-regulation of TGF?2 expression prevented Hh signaling-dependent osteoblast differentiation and motor neuron differentiation. Furthermore, inhibition of TGF? signaling by TGF? receptor I inhibitor SD208 significantly reduced tumor area in K14cre/R26SmoM2 mice. Tumor shrinkage in mice was associated with an increased number of lymphocytes, suggesting an immune suppression role of TGF? signaling. The relevance of our results to human cancer is reflected by the fact that human basal cell carcinomas, which almost always harbor activated Hh signaling, have activated TGF? signaling, as indicated by high levels of phosphorylated SMAD2 and SMAD3 in tumor and stroma. Together, our data indicate that TGF? signaling is critical for Hh signaling-mediated carcinogenesis.

SUBMITTER: Fan Q 

PROVIDER: S-EPMC2978585 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature