Src-family tyrosine kinases (SFKs) regulate cell proliferation, and increased SFK activity is common in human carcinomas, including cutaneous squamous cell carcinomas and its precursors. The elevated SFK activity in cutaneous SCCs was modeled using keratin 14-Fyn Y528F transgenic mice, which spontaneously form punctate keratotic lesions, scaly plaques, and large tumors resembling actinic keratoses (AKs), carcinoma in situ (SCIS), and SCCs, respectively.
Lesional tissue demonstrated increased levels of activated SFKs, PDK-1, STAT-3, and Erk1/2 while Notch 1/NICD protein and transcript levels were decreased. p53 levels also were decreased in SCIS and SCCs.
Raising Srcasm levels using a K14-Fyn Y528F/K14-Srcasm double transgenic model markedly inhibited cutaneous neoplasia. In contrast, increased expression of a non-phosphorylatable Srcasm mutant maintained the neoplastic phenotype. Raising Srcasm levels decreased levels of Fyn, activated SFKs, Erk 1/2, PDK-1, and phospho-STAT3, and raised Notch 1/NICD and p53 levels.
Analysis of human specimens revealed that levels of Fyn and activated SFKs were elevated in SCCs compared with adjacent non-lesional epidermis. In addition, Notch 1 and Srcasm protein and transcript levels were decreased in human SCCs compared to non-lesional epidermis. Therefore, the SCCs produced by the Fyn Y528F mice resemble their human counterparts at the molecular level.
K14-Fyn Y528F mice represent a robust model of cutaneous carcinogenesis that manifests precancerous lesions and SCCs resembling human disease. The Fyn/Srcasm signaling nexus modulates activity of STAT-3, PDK-1, Erk 1/2, Notch 1 and p53. Further study of Fyn and Srcasm should provide insights into the mechanisms regulating keratinocyte proliferation and skin carcinogenesis.