鳞状细胞癌(SCC)是人类最常见的皮肤癌形式之一,神经Wiskott-Aldrich综合征蛋白(N-WASP)在表皮稳态中起着至关重要的作用。为了阐明N-WASP在皮肤癌中的作用,我们产生的小鼠在他莫昔芬(TAM)注射后通过纯合(N-WASPKOG12D)或杂合(N-WASPHetG12D)N-WASP敲除在角质形成细胞中表达组成型活性KRas(KRasG12D)。N-WASPKOG12D和N-WASPHetG12D小鼠在注射TAM之前具有相似的体重并且没有先天性畸形。注射后2周内,N-WASPKOG12D小鼠的体重显着降低,同时在许多部位可见肿瘤,与N-WASPHetG12D小鼠不同,没有可见的肿瘤。我们发现两组老鼠都有油性,接触TAM3周后,皮肤粘稠,眼睛湿润,表明皮脂/meibum的生产过剩。在TAM注射后37天,有几个值得注意的观察。从N-WASPKOG12D小鼠收集的肿瘤具有在N-WASPHetG12D小鼠中未观察到的小到大尺寸的角蛋白珍珠。Western印迹和免疫染色分析都突出了SCC标志物的表达水平显著较高。例如N-WASPKOG12D小鼠的肿瘤中的细胞角蛋白8、17、18和19以及TP63。此外,我们注意到EGFR的表达水平增加,P-ERK,GLUT1,P-mTOR,N-WASPKOG12D小鼠的P-4EBP,表明角质形成细胞中N-WASP的缺失增强了KRas信号传导和葡萄糖摄取,导致侵袭性肿瘤的形成。有趣的是,仅在N-WASPKOG12D小鼠中观察到食道和舌头内的表皮层增厚。PCNA的免疫染色强调了N-WASPKOG12D小鼠皮肤中PCNA阳性细胞的数量明显高于其对应物。这意味着表皮增厚和肿瘤发生增强是由于角质形成细胞的增殖增加。通过我们的结果,我们已经确定N-WASP在皮肤癌中起肿瘤抑制作用.
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-WASPKOG12D and N-WASPHetG12D mice had similar body weights and no congenital malformations prior to the injection of TAM. Within 2 weeks of the injections, the N-WASPKOG12D mice exhibited significant reductions in weight coupled with visible tumors at numerous sites, unlike the N-WASPHetG12D mice, 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-WASPKOG12D mice had small- to large-sized keratin pearls that were not observed in the N-WASPHetG12D mice. 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-WASPKOG12D mice 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-WASPKOG12D mice, 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-WASPKOG12D mice. Immunostaining for PCNA emphasized a significantly higher number of PCNA-positive cells in the skin of the N-WASPKOG12D mice 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.