PTEN/PI3K-Akt Involvement in BCC
There are several reports of a synergistic role of the phosphoinositide-3-kinase (PI3K)-Akt pathway and deregulated Hh signaling in the regulation of neuronal precursor cell cycle progression and in the development of murine tumors, such as medulloblastoma and rhabdomyosarcoma.[128–132] Phosphatase and tensin homolog (PTEN), a highly effective tumor suppressor gene in a variety of tumor tissues, functions by negatively regulating the PI3K-Akt signaling pathway. PI3K, acting through Akt, positively regulates Hh signaling by controlling protein-kinase-A-mediated Gli2 inactivation and turnover. Loss of PTEN in Hh-dependent tumors would upregulate PI3K activity to stimulate even low-level ligand-dependent or constitutive Hh signaling caused by mutations in Hh pathway components. Thus, PTEN function is critical for Hh signaling in embryonic development and in Hh-dependent tumorigenesis.
PTEN is a tumor suppressor for skin cancer in humans and mice.[136–138] Germline mutation of PTEN causes Cowden syndrome, associated with unregulated cellular proliferation and tumor development in the skin and other tissues/organs. Multiple trichilemmomas, that is, benign tumors derived from the ORS epithelium of hair follicles, are characteristic of the skin of these patients. However, deletion of 10q23, where PTEN is located, was found to be an infrequent event in human BCC. This suggests that other mechanisms of PTENinactivation might be involved in BCC tumorigenesis.
As a corollary, it has been demonstrated that UVR, the major etiologic factor for BCC, suppresses PTEN expression, and that this decrease is required for enhanced cell survival in transformed human keratinocytes, indicating that PTEN might be the critical target for UV-induced skin tumorigenesis.
Future Oncol. 2010;6(6):1003-1014. © 2010 Future Medicine Ltd.
Cite this: Basal Cell Carcinoma and the Carcinogenic Role of Aberrant Hedgehog Signaling - Medscape - Jun 01, 2010.