Srcasm inhibits Fyn-induced cutaneous carcinogenesis with modulation of Notch1 and p53.
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.
Zhao
Liang
L
Department of Dermatology, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104, USA.
Li
Weijie
W
Marshall
Christine
C
Griffin
Thomas
T
Hanson
Matthew
M
Hick
Ryan
R
Dentchev
Tzvete
T
Williams
Erik
E
Werth
Adrienne
A
Miller
Christopher
C
Bashir
Hasan
H
Pear
Warren
W
Seykora
John T
JT
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D010766:Phosphorylation; D011230:Precancerous Conditions / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D019061:src-Family Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C497762:Notch1 protein, mouse; D012333:RNA, Messenger; D051881:Receptor, Notch1; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C447618:Tom1L1 protein, mouse; D016159:Tumor Suppressor Protein p53; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases