Squamous cell carcinoma (SCC) is one of the most common forms of skin cancer in humans, and Neural Wiskott-Aldrich Syndrome Protein (N-WASP) plays a crucial role in epidermal homeostasis. To elucidate the role of N-WASP in skin cancer, we generated mice which expressed constitutively active KRas (KRasG12D) in keratinocytes with either homozygous (N-WASPKOG12D) or heterozygous (N-WASPHetG12D) N-WASP knockout upon Tamoxifen (TAM) injection. Both the N-WASPKOG12Dand N-WASPHetG12Dmice had similar body weights and no congenital malformations prior to the injection of TAM. Within 2 weeks of the injections, the N-WASPKOG12Dmice exhibited significant reductions in weight coupled with visible tumors at numerous sites, unlike the N-WASPHetG12Dmice, which had no visible tumors. We found that both sets of mice had oily, sticky skin and wet eyes 3 weeks after their exposure to TAM, indicating the overproduction of sebum/meibum. At 37 days post TAM injection, several notable observations were made. Tumors collected from the N-WASPKOG12Dmice had small- to large-sized keratin pearls that were not observed in the N-WASPHetG12Dmice. A Western blot and immunostaining analysis both highlighted significantly higher levels of expression of SCC markers, such as the cytokeratins 8, 17, 18, and 19 and TP63, in the tumors of the N-WASPKOG12Dmice compared to those of the latter group. Furthermore, we noted increases in the expression levels of EGFR, P-ERK, GLUT1, P-mTOR, and P-4EBP in the N-WASPKOG12Dmice, suggesting that the deletion of N-WASP in the keratinocytes enhanced KRas signaling and glucose uptake, resulting in aggressive tumor formation. Interestingly, a thickening of the epidermal layer within the esophagus and tongue was only observed in the N-WASPKOG12Dmice. Immunostaining for PCNA emphasized a significantly higher number of PCNA-positive cells in the skin of the N-WASPKOG12Dmice compared to their counterparts, implying that epidermal thickening and enhanced tumorigenesis are due to an increased proliferation of keratinocytes. Through our results, we have established that N-WASP plays a tumor-suppressive role in skin cancer.
鳞状细胞癌是人类最常见的皮肤癌类型之一，而神经Wiskott-Aldrich综合征蛋白在表皮稳态中起着关键作用。为阐明N-WASP在皮肤癌中的作用，我们构建了在角质形成细胞中表达持续活化KRas（KRasG12D）的小鼠模型，并通过他莫昔芬注射实现N-WASP的纯合（N-WASPKOG12D）或杂合（N-WASPHetG12D）敲除。两组小鼠在注射前体重相近且无先天畸形。注射后两周内，N-WASPKOG12D小鼠出现显著体重下降并伴有多部位可见肿瘤，而N-WASPHetG12D小鼠未见明显肿瘤。注射三周后，两组小鼠均出现皮肤油性黏腻及眼部湿润现象，提示皮脂/睑板腺分泌过度。注射37天后观察到以下重要结果：N-WASPKOG12D小鼠肿瘤组织中存在未见于对照组的、大小不等的角化珠；Western blot和免疫染色分析均显示，与对照组相比，N-WASPKOG12D小鼠肿瘤中细胞角蛋白8、17、18、19及TP63等鳞癌标志物表达显著升高。此外，N-WASPKOG12D小鼠EGFR、P-ERK、GLUT1、P-mTOR和P-4EBP表达水平上升，表明角质形成细胞中N-WASP缺失可增强KRas信号传导与葡萄糖摄取，进而促进侵袭性肿瘤形成。值得注意的是，仅N-WASPKOG12D小鼠出现食管与舌部表皮层增厚现象。PCNA免疫染色显示其表皮中阳性细胞数显著高于对照组，提示表皮增厚与肿瘤发生增强源于角质形成细胞增殖加速。本研究证实N-WASP在皮肤癌中发挥肿瘤抑制作用。
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