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.