Jacob J Owen and Fen Wang

Introduction. Basal cell carcinoma (BCC) is the most common type of skin cancer, making it the most common human cancer worldwide. BCCs are characterized by unregulated growth of a keratinocyte precursor cell in the epidermis of the skin. The cost of skin cancer has been increasing. The main risk factor for developing BCC is exposure to UV-B light. BCCs present as an enlarging nodule or papule on the surface of the skin that will not heal and may bleed.¹ Current practice is to diagnose with a biopsy specimen² and treat with surgical excision or chemotherapies for advanced metastatic carcinomas.³ The hedgehog signaling pathway is activated in almost every case of BCC. However, this pathway is poorly understood in BCCs. Furthermore, less invasive treatments for BCCs have yet to be developed and implemented into current practice. Our hypothesis is that the hedgehog signaling pathway and other pathways leading to cell growth are dysregulated in BCCs. Methods. We reviewed data from studies on hedgehog signaling molecules and other alternative pathways in basal cell carcinomas. Methodology included RNA extraction and real-time PCR,^4,5 immunohistochemical staining and analysis,^4,6,7 and development of short-hairpin RNA with western blot analysis.⁸ Results. RNA of hedgehog signaling molecules glioma-associated oncogene homologue 1 and 2 (GLI1/2), patched 1 and 2 (PTCH1/2), and sonic hedgehog (SHH) is overexpressed in BCCs.⁴ Of these signaling molecules, GLI1 is the most highly expressed in BCCs and is specific for BCCs compared to other skin cancer types.⁴ GLI1 has strong nuclear staining and a moderate cytoplasmic staining.⁶ The expression of the other member of the GLI transcription factor family, GLI2, was increased upon SHANK-associated RH domain-interacting protein (SHARPIN) knockdown.⁸ Overexpressed GLI2 RNA levels were reduced to normal in BCC-associated stromal fibroblasts upon treatment with Sonidegib.⁵ In an alternative growth promoting pathway, the MEK/ERK pathway, activated (phosphorylated) ERK was increased in aggressive versus non-aggressive BCCs.⁷ Conclusions. GLI1, SHANK-associated RH domain-interacting protein (SHARPIN), and phosphorylated extracellular signal-regulated kinase (pERK) are potential therapeutic targets for BCCs. This is because GLI1 is overexpressed in and specific to BCCs,^4,6 SHARPIN controls GLI2 expression levels,⁸ and pERK is upregulated in aggressive BCCs.⁷ These pathways regulate the cell cycle, and dysregulation of these pathways leads to cell proliferation. Sonidegib is a potential non-invasive treatment of BCC-associated fibroblasts that can rescue hedgehog proteins to normal levels.⁵ Furthermore, the MEK/ERK pathway could serve as a potential alternative target pathway in BCCs and warrants further study.⁷

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