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Induction of Sonic Hedgehog Mediators by Transforming Growth Factor-ß: Smad3-Dependent Activation of Gli2 and Gli1 Expression In vitro and In vivo

¹ Institut National de la Sante et de la Recherche Medicale U697, Paris, France; ² Department of Otolaryngology, Oregon Health and Science University, Portland, Oregon; ³ Centre National de la Recherche Scientifique UPR 2169, Institut Gustave-Roussy, Villejuif, France; and ⁴ Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands

Requests for reprints: Alain Mauviel, Institut National de la Sante et de la Recherche Medicale U697, Hôpital Saint-Louis, Pavillon Bazin, 1, Avenue Claude Vellefaux, 75010 Paris, France. Phone: 33-1-53-72-20-69; Fax: 33-1-53-72-20-51; E-mail: alain.mauviel{at}stlouis.inserm.fr.

Hedgehog (Hh) and transforming growth factor-ß (TGF-ß) family members are involved in numerous overlapping processes during embryonic development, hair cycle, and cancer. Herein, we show that TGF-ß induces the expression of the Hh signaling molecules Gli1 and Gli2 in various human cell types, including normal fibroblasts and keratinocytes, as well as various cancer cell lines. Gli2 induction by TGF-ß is rapid, independent from Hh receptor signaling, and requires a functional Smad pathway. Gli1 expression is subsequently activated in a Gli2-dependent manner. In transgenic mice overexpressing TGF-ß1 in the skin, Gli1 and Gli2 expression is also elevated and depends on Smad3. In pancreatic adenocarcinoma cell lines resistant to Hh inhibition, pharmacologic blockade of TGF-ß signaling leads to repression of cell proliferation accompanied with a reduction in Gli2 expression. We thus identify TGF-ß as a potent transcriptional inducer of Gli transcription factors. Targeting the cooperation of Hh and TGF-ß signaling may provide new therapeutic opportunities for cancer treatment. [Cancer Res 2007;67(14):6981–6]

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