The transcription factor Twist1 has been reported to be essential for the formation and invasiveness of chemically induced tumors in mouse skin. However, the impact of keratinocyte‐specific Twist1 deletion on skin carcinogenesis caused by UVB radiation has not been reported. Deletion of Twist1 in basal keratinocytes of mouse epidermis using K5.Cre × Twist1^flox/flox mice led to significantly reduced UVB‐induced epidermal hyperproliferation. In addition, keratinocyte‐specific deletion of Twist1 significantly suppressed UVB‐induced skin carcinogenesis. Further analyses revealed that deletion of Twist1 in cultured keratinocytes or mouse epidermis in vivo led to keratinocyte differentiation. In this regard, deletion of Twist1 in epidermal keratinocytes showed significant induction of early and late differentiation markers, including TG1, K1, OVOL1, loricrin, and filaggrin. Similar results were obtained with topical application of harmine, a Harmala alkaloid that leads to degradation of Twist1. In contrast, overexpression of Twist1 in cultured keratinocytes suppressed calcium‐induced differentiation. Further analyses using both K5.Cre × Twist1^flox/flox mice and an inducible system where Twist1 was deleted in bulge region keratinocytes showed loss of expression of hair follicle stem/progenitor markers, including CD34, Lrig1, Lgr5, and Lgr6. These data support the conclusion that Twist1 has a direct role in maintaining the balance between proliferation and differentiation of keratinocytes and keratinocyte stem/progenitor populations. Collectively, these results demonstrate a critical role for Twist1 early in the process of UVB skin carcinogenesis, and that Twist1 may be a novel target for the prevention of cutaneous squamous cell carcinoma.

中文翻译：

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Twist1 是 UVB 诱导的鳞状细胞癌发展所必需的

据报道，转录因子 Twist1 对小鼠皮肤中化学诱导肿瘤的形成和侵袭至关重要。然而，尚未报道角质形成细胞特异性 Twist1 缺失对 UVB 辐射引起的皮肤癌发生的影响。使用 K5.Cre × Twist1 ^{flox/flox 删除小鼠表皮基底角质形成细胞中的 Twist1}小鼠导致UVB诱导的表皮过度增殖显着减少。此外，Twist1 的角质形成细胞特异性缺失显着抑制了 UVB 诱导的皮肤癌发生。进一步的分析表明，体内培养的角质形成细胞或小鼠表皮中 Twist1 的缺失导致角质形成细胞分化。在这方面，表皮角质形成细胞中 Twist1 的缺失显示了早期和晚期分化标志物的显着诱导，包括 TG1、K1、OVOL1、loricrin 和丝聚蛋白。局部应用harmine（一种导致Twist1降解的Harmala生物碱）也获得了类似的结果。相反，Twist1 在培养的角质形成细胞中的过表达抑制了钙诱导的分化。使用 K5.Cre × Twist1 ^{flox/flox进行进一步分析}小鼠和一个在凸起区域角质形成细胞中缺失 Twist1 的诱导系统显示毛囊干/祖细胞标志物（包括 CD34、Lrig1、Lgr5 和 Lgr6）的表达缺失。这些数据支持 Twist1 在维持角质形成细胞和角质形成细胞干/祖细胞群的增殖和分化之间的平衡方面具有直接作用的结论。总的来说，这些结果证明了 Twist1 在 UVB 皮肤癌发生过程中早期的关键作用，并且 Twist1 可能是预防皮肤鳞状细胞癌的新靶点。