Open AccessSonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes
Author(s) -
Monica Dentice,
Cristina Luongo,
Stephen A. Huang,
Raffaele Ambrosio,
Antonia Elefante,
Delphine MirebeauPrunier,
Ann Marie Zavacki,
Gianfranco Fenzi,
Marina Grachtchouk,
Mark E. Hutchin,
Andrzej A. Dlugosz,
Antonio C. Bianco,
Caterina Missero,
P. Reed Larsen,
Domenico Salvatore
Publication year - 2007
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0706754104
Subject(s) - vismodegib , sonic hedgehog , endocrinology , medicine , hair follicle , biology , cancer research , cyclopamine , thyroid , hedgehog signaling pathway , deiodinase , microbiology and biotechnology , signal transduction , triiodothyronine
The Sonic hedgehog (Shh) pathway plays a critical role in hair follicle physiology and is constitutively active in basal cell carcinomas (BCCs), the most common human malignancy. Type 3 iodothyronine deiodinase (D3), the thyroid hormone-inactivating enzyme, is frequently expressed in proliferating and neoplastic cells, but its role in this context is unknown. Here we show that Shh, through Gli2, directly induces D3 in proliferating keratinocytes and in mouse and human BCCs. We demonstrate that Gli-induced D3 reduces intracellular active thyroid hormone, thus resulting in increased cyclin D1 and keratinocyte proliferation. D3 knockdown caused a 5-fold reduction in the growth of BCC xenografts in nude mice. Shh-induced thyroid hormone degradation via D3 synergizes with the Shh-mediated reduction of the type 2 deiodinase, the thyroxine-activating enzyme, and both effects are reversed by cAMP. This previously unrecognized functional cross-talk between Shh/Gli2 and thyroid hormone in keratinocytes is a pathway by which Shh produces its proliferative effects and offers a potential therapeutic approach to BCC.