Wednesday, April 24, 2024
4/24/2024
PROJECT SUMMARY/ABSTRACT Although the number of new cases of BCC has increased rapidly each year in the last few decades, the molecular basis of its pathogenesis is not completely understood. Activation of Hedgehog (Hh) signaling pathway was shown to be a key factor driving the development of BCC. Experimentation with transgenic mouse models have provided evidence that activation of the transcription factor GLI1 is a key step in the initiation of the tumorigenic program leading to BCC. The Wnt/¿-catenin signaling pathway was also shown to be activated in BCCs. Wnt and Hh signaling pathways have been postulated to interact or cross regulate at multiple levels, yet the mechanisms of these interactions are not clear. We recently identified a novel mechanism by which Wnt/¿- catenin signaling induces expression of the Hh transcriptional activator GLI1. We showed that the RNA binding protein CRD-BP, a direct target of the Wnt/¿-catenin signaling, binds to GLI1 mRNA, stabilizes it, upregulates its levels and activities. This regulation of GLi1 by CRD-BP is independent of the upstream Hh signal. CRD-BP is overexpressed in BCCs and emerges as an attractive target in the treatment of BCCs including SMO inhibitor resistant BCCs. Our hypothesis is that Wnt-induced and CRD-BP-dependent regulation of GLI1 expression and activities is important to the development and progression of BCCs. Our objective is to delineate the role of CRD-BP in BCC tumorigenesis by determining its contribution to the tumorigenic phenotype of human BCC cells. We also plan to analyze the role of CRD-BP in BCC development and progression in vivo using our unique mouse model CRD-BP-loxP and the BCC mouse model Ptch+/-. This study proposes a novel molecular mechanism by which Wnt signaling and CRD-BP modulate the transcriptional outcome of the Hh signaling and promote BCC development. We also propose a novel approach in the treatment of BCC; this involves inhibition of CRD-BP which is involved in activation of anti-apoptotic pathways and induction of multidrug resistance membrane transporters. In this study we will use unique tools (the BCC cell line UW-BCC1, CRD-BP loxP mouse model, and the BCC mouse model Ptch+/-) to test our hypothesis. Overall, the completion of this study will delineate the role of CRD-BP in BCC tumorigenesis. This may potentially lead to design of the new agents effective in the treatment of BCCs, including advanced, inoperable, or SMO inhibitor resistant BCCs. This would alleviate the cost of care for BCCs and reduce the morbidity associated with the advanced form of this disease.
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