Basal Cell Carcinoma and the Carcinogenic Role of Aberrant Hedgehog Signaling

Anna Saran

Disclosures

Future Oncol. 2010;6(6):1003-1014. 

In This Article

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,[133] functions by negatively regulating the PI3K-Akt signaling pathway.[134] 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.[135] 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.[136] Multiple trichilemmomas, that is, benign tumors derived from the ORS epithelium of hair follicles, are characteristic of the skin of these patients.[139] However, deletion of 10q23, where PTEN is located, was found to be an infrequent event in human BCC.[140] 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,[141] indicating that PTEN might be the critical target for UV-induced skin tumorigenesis.

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