Requirement of TGF β signaling for SMO-mediated carcinogenesis

Qipeng Fan, Miao He, Tao Sheng, Xiaoli Zhang, Mala Sinha, Bruce Luxon, Xingbo Zhao, Jingwu Xie

    Research output: Contribution to journalArticle

    42 Citations (Scopus)

    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 TGFβ2 as a major Hh-regulated gene. TGFβ2 expression was high in the keratinocytes, with activated TGFβ signaling (indicated by elevated expression of phosphorylated SMAD2/3) detected in both tumor and stroma. The significance of TGFβ signaling for SMO function was demonstrated in two assays. Down-regulation of TGFβ2 expression prevented Hh signaling-dependent osteoblast differentiation and motor neuron differentiation. Furthermore, inhibition of TGFβ signaling by TGFβ 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 TGFβ 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 TGFβ signaling, as indicated by high levels of phosphorylated SMAD2 and SMAD3 in tumor and stroma. Together, our data indicate that TGFβ signaling is critical for Hh signaling-mediated carcinogenesis.

    Original languageEnglish (US)
    Pages (from-to)36570-36576
    Number of pages7
    JournalJournal of Biological Chemistry
    Volume285
    Issue number47
    DOIs
    StatePublished - Nov 19 2010

    Fingerprint

    Hedgehogs
    Carcinogenesis
    Basal Cell Carcinoma
    Neoplasms
    Tumors
    Lymphocyte Count
    Motor Neurons
    Transducers
    Osteoblasts
    Keratinocytes
    Embryonic Development
    Cells
    Transcription Factors
    Down-Regulation
    Lymphocytes
    Ports and harbors
    Neurons
    Assays
    Genes

    ASJC Scopus subject areas

    • Biochemistry
    • Cell Biology
    • Molecular Biology
    • Medicine(all)

    Cite this

    Fan, Q., He, M., Sheng, T., Zhang, X., Sinha, M., Luxon, B., ... Xie, J. (2010). Requirement of TGF β signaling for SMO-mediated carcinogenesis. Journal of Biological Chemistry, 285(47), 36570-36576. https://doi.org/10.1074/jbc.C110.164442

    Requirement of TGF β signaling for SMO-mediated carcinogenesis. / Fan, Qipeng; He, Miao; Sheng, Tao; Zhang, Xiaoli; Sinha, Mala; Luxon, Bruce; Zhao, Xingbo; Xie, Jingwu.

    In: Journal of Biological Chemistry, Vol. 285, No. 47, 19.11.2010, p. 36570-36576.

    Research output: Contribution to journalArticle

    Fan, Q, He, M, Sheng, T, Zhang, X, Sinha, M, Luxon, B, Zhao, X & Xie, J 2010, 'Requirement of TGF β signaling for SMO-mediated carcinogenesis', Journal of Biological Chemistry, vol. 285, no. 47, pp. 36570-36576. https://doi.org/10.1074/jbc.C110.164442
    Fan Q, He M, Sheng T, Zhang X, Sinha M, Luxon B et al. Requirement of TGF β signaling for SMO-mediated carcinogenesis. Journal of Biological Chemistry. 2010 Nov 19;285(47):36570-36576. https://doi.org/10.1074/jbc.C110.164442
    Fan, Qipeng ; He, Miao ; Sheng, Tao ; Zhang, Xiaoli ; Sinha, Mala ; Luxon, Bruce ; Zhao, Xingbo ; Xie, Jingwu. / Requirement of TGF β signaling for SMO-mediated carcinogenesis. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 47. pp. 36570-36576.
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