Role of CRD-BP in Basal Cell Carcinoma Development

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DESCRIPTION (provided by applicant): Basal cell carcinoma (BCC) is the most common form of skin cancer, affecting approximately one million Americans each year. Its cost of care represents the fifth highest for all cancers in the Medicare population in the United States. 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. Transgenic mouse models 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. Canonical Wnt/¿-catenin signaling is involved in the BCC tumorigenesis perhaps by modulating the Hh pathway activity. Wnt and Hh are two major pathways that are critical in embryonic development, stem cell maintenance, and tumorigenesis. These two pathways have been postulated to interact or cross regulate at multiple levels, yet the mechanisms of these interactions are not clear. In our preliminary studies, we identified a novel mechanism by which Wnt signaling regulates the transcriptional outcome of Hh signaling pathway. We demonstrated that Wnt/¿-catenin signaling induces expression of the Hh transcriptional activator GLI1. We showed that CRD-BP, a direct target of the Wnt/¿-catenin signaling, binds to the segment of the coding region of GLI1 mRNA and stabilizes it. We also showed that Wnt/¿-catenin signaling induces the expression and transcriptional activity of GLI1 in a CRD-BP dependent manner. We hypothesize that Wnt-induced and CRD- BP-dependent regulation of GLI1 expression and activities is important to the development of BCCs. We propose to delineate the role of CRD-BP in BCC tumorigenesis. Pursuant to these goals, the specific aims are: (1) To analyze the expression of CRD-BP and the activity of Wnt and Hh signaling pathways in BCC. (2) To determine whether CRD-BP expression affects keratinocyte proliferation. (3) To analyze whether CRD-BP- dependent regulation of GLI1 involves translational pausing and/or, microRNA. Overall, the completion of these studies will be the first step in delineating the role of CRD-BP in BCC development. The results of this proposal will be used as a basis for future extramurally funded comprehensive analysis on the role of CRD-BP in the genesis of BCCs. Public Health Relevance: These studies may potentially lead to design of the agents capable of inhibiting CRD-BP function and effective in the treatment of BCCs. This would significantly decrease the cost of care for BCCs and be a beneficial alternative to repeated surgical procedures especially for patients who are at high risk for multiple basal-cell tumors including people with heritable disorder basal cell nevus syndrome (BCNS) and immunocompromised patients. PUBLIC HEALTH RELEVANCE: Approximately one million Americans each year are affected by the skin cancer basal cell carcinoma. Its cost of care represents the fifth highest for all cancers in the Medicare population in the United States. The protein GLI1 is important for the development of basal cell carcinoma. We have identified a new mechanism leading to the stimulation of expression and activity of GLI1. We plan to study whether the newly-discovered mechanism is important for basal cell carcinoma development. This would be significant in developing new ways of treating basal cell carcinoma and reduce its cost of care.