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Published on: December 19, 2019
Srcasm inhibits Fyn-induced cutaneous carcinogenesis with modulation of Notch1 and p53
Liang Zhao1, Weijie Li, Christine Marshall
1Department of Dermatology, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104, USA.
Abstract:
Src family tyrosine kinases (SFK) regulate cell proliferation, and increased SFK activity is common in human carcinomas, including cutaneous squamous cell carcinomas (SCC) and its precursors. The elevated SFK activity in cutaneous SCCs was modeled using K14-Fyn Y528F transgenic mice, which spontaneously form punctate keratotic lesions, scaly plaques, and large tumors resembling actinic keratoses, SCC in situ, and SCCs, respectively. Lesional tissue showed increased levels of activated SFKs, PDK1, STAT3, and ERK1/2, whereas Notch1/NICD protein and transcript levels were decreased. p53 levels also were decreased in SCC in situ and SCCs. Increasing Srcasm levels using a K14-Fyn Y528F/K14-Srcasm double transgenic model markedly inhibited cutaneous neoplasia. In contrast, increased expression of a nonphosphorylatable Srcasm mutant maintained the neoplastic phenotype. Increasing Srcasm levels decreased levels of Fyn, activated SFKs, ERK1/2, PDK1, and phospho-STAT3, and increased Notch1/NICD and p53 levels. Analysis of human specimens revealed that levels of Fyn and activated SFKs were elevated in SCCs compared with adjacent nonlesional epidermis. In addition, Notch1 and Srcasm protein and transcript levels were decreased in human SCCs compared with nonlesional 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 STAT3, PDK1, ERK1/2, Notch1, and p53. Further study of Fyn and Srcasm should provide insights into the mechanisms regulating keratinocyte proliferation and skin carcinogenesis.
Insights
Increased Src kinase activity drives skin cancer (cutaneous squamous cell carcinoma). Restoring Srcasm levels in a mouse model suppressed tumor growth and restored protective proteins, offering new therapeutic targets for skin cancer.
Area of Science:
- Oncology
- Dermatology
- Molecular Biology
- Cancer Research
Background:
- Src family tyrosine kinases (SFK) are crucial regulators of cell proliferation.
- Elevated SFK activity is a common hallmark of human carcinomas, particularly cutaneous squamous cell carcinomas (SCC).
- Understanding the molecular mechanisms underlying SCC development is vital for therapeutic advancements.
Purpose of the Study:
- To investigate the role of Fyn and Srcasm in cutaneous squamous cell carcinoma (SCC) development.
- To establish and characterize a transgenic mouse model that recapitulates human SCC.
- To explore the therapeutic potential of modulating Srcasm levels in skin carcinogenesis.
Main Methods:
- Utilized K14-Fyn Y528F transgenic mice to model elevated SFK activity in cutaneous SCC.
- Developed a K14-Fyn Y528F/K14-Srcasm double transgenic model to assess Srcasm's inhibitory effects.
- Analyzed protein and transcript levels of key signaling molecules (SFKs, PDK1, STAT3, ERK1/2, Notch1, p53) in mouse models and human SCC specimens.
Main Results:
- K14-Fyn Y528F mice spontaneously developed lesions mimicking human actinic keratoses and SCCs.
- Increased Srcasm levels in double transgenic mice significantly inhibited skin neoplasia, reducing Fyn, activated SFKs, ERK1/2, PDK1, and phospho-STAT3.
- Restoring Srcasm increased levels of Notch1/NICD and p53, while human SCCs showed elevated Fyn/activated SFKs and decreased Notch1/Srcasm compared to normal skin.
Conclusions:
- The K14-Fyn Y528F mouse model accurately reflects human cutaneous SCC at the molecular level.
- The Fyn/Srcasm signaling pathway is a critical modulator of key pathways (STAT3, PDK1, ERK1/2, Notch1, p53) in skin carcinogenesis.
- Targeting Fyn and Srcasm presents a promising therapeutic strategy for inhibiting keratinocyte proliferation and treating skin cancer.
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