Ultraviolet irradiation represses PATCHED gene transcription in human epidermal keratinocytes through an activator...

Area of Science:

• Oncology
• Molecular Biology
• Dermatology

Background:

• Basal cell carcinoma (BCC) is a common skin cancer originating from keratinocytes.
• The SONIC HEDGEHOG pathway is consistently deregulated in BCC, with PATCHED receptor overexpression observed in all cases.
• Ultraviolet B (UVB) irradiation is a known risk factor for BCC development.

Purpose of the Study:

• To investigate the effect of UVB irradiation on PATCHED gene expression in basal cell carcinoma.
• To elucidate the molecular mechanisms underlying UVB-induced regulation of the PATCHED gene.

Main Methods:

• Reverse transcription-PCR was used to analyze PATCHED mRNA levels after UVB exposure in vitro and ex vivo.
• Reporter gene assays were performed to assess the transcriptional activity of the human PATCHED gene's 5'-regulatory region following UVB irradiation.
• Experiments involving c-JUN overexpression and knockout mouse embryonic fibroblasts were conducted to evaluate the role of the AP-1 pathway.

Main Results:

• UVB irradiation significantly decreased PATCHED mRNA levels both in vitro and ex vivo.
• Transcription of the PATCHED gene, driven by its 5'-regulatory region, was down-regulated by UVB.
• Overexpression of c-JUN repressed the PATCHED promoter, and this effect was confirmed in c-JUN NH(2)-terminal protein kinase knockout cells, indicating AP-1 pathway involvement.

Conclusions:

• UVB irradiation induces down-regulation of the tumor suppressor PATCHED at the transcriptional level.
• The AP-1 oncogenic pathway plays a critical role in mediating UVB-induced repression of PATCHED.
• These findings provide the first evidence linking UV-induced AP-1 activation to the transcriptional down-regulation of PATCHED in the context of BCC.