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The delta isoform of Protein Kinase C (PKC- ) is a potential tumor suppressor gene for human squamous cell carcinomas (SCCs). The objective of this study is to investigate the mechanism of PKC- loss in human SCCs. We used Laser Capture Microdissection to isolate cells for nucleic acid analysis from normal epidermises and human SCCs. Using this approach, we found that PKC- is lost at the mRNA level in human SCCs, and that the PKC- gene is rarely deleted suggesting that the mechanism of down-regulation of PKC- in SCCs is at the level of gene transcription. Further investigation identified a novel Ras PI3K Fyn NF- B signaling pathway necessary and suffcicient for PKC- repression in human keratinocytes. Our results have implications for the development of therapeutic strategies abrogating this signaling pathway to trigger the re-expression of pro-apoptotic PKC- to induce apoptosis in SCCs.