Institute of Photomedicine, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, 200443, China.
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China.
Cell Death Dis. 2021 Mar 4;12(3):247. doi: 10.1038/s41419-021-03525-x.
Cutaneous squamous cell carcinoma (cSCC) is prevalent in the world, accounting for a huge part of non-melanoma skin cancer. Most cSCCs are associated with a distinct pre-cancerous lesion, the actinic keratosis (AK). However, the progression trajectory from normal skin to AK and cSCC has not been fully demonstrated yet. To identify genes involved in this progression trajectory and possible therapeutic targets for cSCC, here we constructed a UV-induced cSCC mouse model covering the progression from normal skin to AK to cSCC, which mimicked the solar UV radiation perfectly using the solar-like ratio of UVA and UVB, firstly. Then, transcriptome analysis and a series of bioinformatics analyses and cell experiments proved that Rorα is a key transcript factor during cSCC progression. Rorα could downregulate the expressions of S100a9 and Sprr2f in cSCC cells, which can inhibit the proliferation and migration in cSCC cells, but not the normal keratinocyte. Finally, further animal experiments confirmed the inhibitory effect of cSCC growth by Rorα in vivo. Our findings showed that Rorα would serve as a potential novel target for cSCC, which will facilitate the treatment of cSCC in the future.
皮肤鳞状细胞癌（cSCC）在世界范围内普遍存在，占非黑色素瘤皮肤癌的很大一部分。大多数 cSCC 与一种明显的癌前病变——光化性角化病（AK）有关。然而，从正常皮肤到 AK 和 cSCC 的进展轨迹尚未完全阐明。为了确定参与这一进展轨迹的基因和 cSCC 的可能治疗靶点，我们在这里构建了一个 UV 诱导的 cSCC 小鼠模型，涵盖了从正常皮肤到 AK 到 cSCC 的进展过程，该模型首先使用类似于太阳的 UVA 和 UVB 比率完美模拟了太阳紫外线辐射。然后，转录组分析和一系列生物信息学分析和细胞实验证明，Rorα 是 cSCC 进展过程中的关键转录因子。Rorα 可以下调 cSCC 细胞中 S100a9 和 Sprr2f 的表达，从而抑制 cSCC 细胞的增殖和迁移，但对正常角质形成细胞没有影响。最后，进一步的动物实验证实了 Rorα 在体内对 cSCC 生长的抑制作用。我们的研究结果表明，Rorα 将成为 cSCC 的一个潜在的新靶点，这将有助于未来 cSCC 的治疗。
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