Abstract C14: The thyroid hormone-sonic hedgehog cross-talk in the tumorigenesis of basal cell carcinoma cells

Abstract

Abstract The pro-hormone, thyroxine (T4), must be converted into T3 in order to be active. This metabolic process has been increasingly recognized as an essential mechanism that regulates thyroid hormone (TH) action at cellular level. TH action is regulated by the activity of the deiodinases, which can either activate (D1, D2) or inactivate (D3) the prohormone. The Sonic hedgehog (Shh) pathway plays a critical role in tumor development, In skin, constitutive Shh signaling causes basal cell carcinoma (BCCs) the most common cancer in humans. We have recently demonstrated that Shh-Gli2 pathway induces D3 in human and mouse BCCs, however the role of D3 and T3-depletion in BCC tumor formation and maintenance is unknown. In the present study we tested the hypothesis that local control of TH action- through regulation of deiodinases- is a necessary step for the action of Shh pathway. To this aim, BCC cells, G2N2c were grown in thyroid hormone deprived media (charcoal serum -CS), or CS plus exogenous T3 at different concentrations. We observed a reduction in the growing rate directly correlated to the concentrations of T3 in the media. Furthermore, in the same cells, T3 interferes specifically and directly with Gli2 expression, by reducing Gli2 protein level and activity. These data, together with the finding that Gli2 mRNA does not change in the same setting, indicate that T3 reduced Gli-2 protein at post-transcriptional level. Finally, to study the effect of thyroid hormone on the BCC tumor growth in vivo, we injected nude mice with BCC cells and treated the resulting tumors with a T3-based cream. Tumor weight, showed a significative reduction in tumors size when topically T3-treated. In conclusion, we highlight a functional cross-talk between thyroid hormone and the Shh-signalling in BCC cells. This mechanism could have broad implications, not only to understand the general role of hormones, in particular T3, in the process of tumor formation and growth, but also may lead to the identification of novel therapeutic approaches aimed at interfering with these signals in a pathological context. Citation Information: Cancer Res 2009;69(23 Suppl):C14.