Srcasm inhibits Fyn-induced cutaneous carcinogenesis with modulation of Notch1 and p53.
Srcasm inhibits Fyn-induced cutaneous carcinogenesis with modulation of Notch1 and p53.
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DOI：
10.1158/0008-5472.can-09-2976
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发表时间：
2009-12-15
期刊：
影响因子：
11.2
通讯作者：
Seykora JT
中科院分区：
文献类型：
--
作者：
Zhao L;Li W;Marshall C;Griffin T;Hanson M;Hick R;Dentchev T;Williams E;Werth A;Miller C;Bashir H;Pear W;Seykora JT
Src家族酪氨酸激酶（SFKs）调节细胞增殖，并且增加的SFK活性在人类癌症中是常见的，包括皮肤鳞状细胞癌及其前体。使用角蛋白14-Fyn Y 528 F转基因小鼠对皮肤SCC中升高的SFK活性进行建模，所述转基因小鼠自发形成分别类似于光化性角化病（AK）、原位癌（SCIS）和SCC的点状角化病变、鳞状斑块和大肿瘤。病变组织显示出激活的SFKs、PDK-1、STAT-3和Erk 1/2水平升高，而Notch 1/NICD蛋白和转录水平降低。SCIS和SCC中p53水平也降低。使用K14-Fyn Y 528 F/K14-Srcasm双转基因模型提高Srcasm水平显著抑制皮肤瘤形成。相反，非磷酸化Srcasm突变体的表达增加维持了肿瘤表型。升高Srcasm水平降低Fyn、活化的SFKs、Erk 1/2、PDK-1和磷酸化STAT 3的水平，并升高Notch 1/NICD和p53水平。对人类样本的分析显示，与邻近的非病变表皮相比，SCC中Fyn和活化SFKs的水平升高。此外，与非病变表皮相比，Notch 1和Srcasm蛋白和转录物水平在人SCC中降低。因此，由Fyn Y 528 F小鼠产生的SCC在分子水平上类似于它们的人类对应物。K14-Fyn Y 528 F小鼠代表了一种稳健的皮肤癌发生模型，其表现出类似于人类疾病的癌前病变和SCC。Fyn/Srcasm信号传导关系调节STAT-3、PDK-1、Erk 1/2、Notch 1和p53的活性。Fyn和Srcasm的进一步研究将为角质形成细胞增殖和皮肤癌发生的调控机制提供新的见解。
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.