A role of PDGFRα in basal cell carcinoma proliferation

Activation of the hedgehog pathway, through the loss of patched (PTC) or the activation of smoothened (SMO), occurs frequently in basal cell carcinoma (BCC), the most common human cancer. However, the molecular basis of this neoplastic effect is not understood. The downstream molecule Gli1 is known to mediate the biological effect of the pathway and is itself up-regulated in all BCCs. Gli1 can drive the production of BCCs in the mouse when overexpressed in the epidermis. Here we show that Gli1 can activate platelet-derived growth factor receptor alpha (PDGFR alpha) in C3H10T(1)/(2) cells. Functional up-regulation of PDGFR alpha by Gli1 is accompanied by activation of the ras-ERK pathway, a pathway associated with cell proliferation. The relevance of this mechanism in vivo is supported by a high level expression of PDGFR alpha in BCCs of mice and humans. In the murine BCC cell line ASZ001, in which both copies of the PTC gene are inactivated, DNA synthesis and cell proliferation can be slowed by re-expression of PTC, which downregulates PDGFR alpha expression, or by downstream inhibition of PDGFR alpha with neutralizing antibodies. Therefore, we conclude that increased expression of PDGFR alpha may be an important mechanism by which mutations in the hedgehog pathway cause BCCs.