A role of PDGFRα in basal cell carcinoma proliferation

Abstract

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 ␣ (PDGFR␣) in C3H10T 1 ⁄2 cells. Functional up-regulation of PDGFR␣ 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␣ 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␣ expression, or by downstream inhibition of PDGFR␣ with neutralizing antibodies. Therefore, we conclude that increased expression of PDGFR␣ may be an important mechanism by which mutations in the hedgehog pathway cause BCCs.

The EWS/FLI1 oncogenic transcription factor deregulates GLI1

“…This finding also demonstrates that HH-GLI signaling can upregulate the PDGF-C ligand in addition to its receptor, PDGFR-a (Xie et al, 2001). This also shows that BMI-1 is regulated by aberrant HH-GLI signaling in NIH3T3, as has been observed in the background of cerebellar development and medulloblastoma (Leung et al, 2004).…”

“…Prior investigations with EWS/FLI1 deregulation of platelet-derived growth factor C (PDGF-C) (Zwerner and May, 2001) directed our attention to evidence in other tumor systems that there could be a link between PDGF pathway deregulation and deregulation of the HH-GLI pathway (Xie et al, 2001;Lokker et al, 2002). To address this possibility, we investigated whether EWS/FLI1 might act to alter this pathway in an NIH3T3 model transformation system.…”

“…Previously, PDGFR-a had been shown to be deregulated by HH signaling but no unregulated ligand was found (Xie et al, 2001). These findings demonstrate that PDGF-C may be such an upregulated ligand.…”

Fibroblast growth factor–hedgehog interdependence during retina regeneration

“…In one report, transient overexpression of Gli1 in C3H10T1/2 cells increased the amount of pErk. Additionally, the pErk increase in C3H10T1/2 cells was inhibited with the MEK-inhibitor U0126 (Xie et al, 2001). In another report, Shh was able to stimulate proliferation of rat gastric cells by means of pErk activation, which was also inhibited by an MEK-inhibitor PD98059 (Osawa et al, 2006).…”

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Thus, we predict that mutations of additional genes in the hedgehog pathway are yet to be discovered in sporadic BCCs. Molecular studies indicate that activated hedgehog signaling in BCCs, leads to cell proliferation through elevated expression of PDGFRa (Xie et al, 2001), whereas targeted inhibition of hedgehog signaling causes apoptosis via Fas induction (Athar et al, 2004).…”