Background/Objectives:Non-melanoma skin cancer (NMSC) is among the most common cancers in the United States, with solar ultraviolet (UV) radiation being a primary etiological factor. T-LAK cell-originated protein kinase (TOPK), a serine/threonine kinase activated by solar UV, has been implicated in skin carcinogenesis. This study aimed to investigate the mechanistic role of TOPK in solar UV-induced skin damage and tumor development.Methods:RNA sequencing (RNA-seq) was performed on skin tissues from wild-type (WT) and TOPK knockout (KO) mice, with or without solar UV exposure, to identify TOPK-regulated genes and pathways. Follow-up experiments using Western blotting, immunofluorescence, and luciferase assays were conducted in vitro and in vivo. Functional assays included 3D spheroid and Transwell co-culture systems involving cutaneous squamous cell carcinoma (cSCC) and fibroblast cells.Results:TOPK deletion altered gene expression profiles and inhibited solar UV-induced activation of multiple signaling pathways, including cytokine–cytokine receptor interaction, PI3K/AKT, MAPKs, PKG, cAMP, and calcium signaling. RNA-seq and protein analyses identified interleukin-19 (IL19) as a key downstream effector suppressed by TOPK deletion. In cSCC and fibroblast cells, TOPK knockdown reduced IL19 expression and secretion. IL19 promoted cSCC growth and activated PI3K/AKT, ERK, and TOPK pathways. Additionally, chronic TGFβ exposure increased IL19 expression and activated fibroblasts, as indicated by elevated αSMA and FAPα levels.Conclusions:These findings establish TOPK as a central regulator of solar UV-induced skin carcinogenesis, partially via modulation of IL19 signaling and fibroblast activation. Targeting TOPK may offer a novel strategy for the prevention and treatment of NMSC.
**背景/目的：** 非黑色素瘤皮肤癌（NMSC）是美国最常见的癌症之一，其中太阳紫外线（UV）辐射是主要病因。T-LAK细胞来源的蛋白激酶（TOPK）是一种受太阳紫外线激活的丝氨酸/苏氨酸激酶，已被证实与皮肤癌发生相关。本研究旨在探讨TOPK在太阳紫外线诱导的皮肤损伤及肿瘤发展中的机制作用。 **方法：** 对野生型（WT）和TOPK敲除（KO）小鼠的皮肤组织（无论是否暴露于太阳紫外线）进行RNA测序（RNA-seq），以识别TOPK调控的基因和通路。随后在体外和体内通过蛋白质印迹、免疫荧光及荧光素酶报告基因实验进行验证。功能实验包括采用三维球体培养和Transwell共培养系统，研究皮肤鳞状细胞癌（cSCC）细胞与成纤维细胞间的相互作用。 **结果：** TOPK缺失改变了基因表达谱，并抑制了太阳紫外线诱导的多种信号通路激活，包括细胞因子-细胞因子受体相互作用、PI3K/AKT、MAPKs、PKG、cAMP及钙信号通路。RNA-seq和蛋白质分析确定白细胞介素-19（IL19）是受TOPK缺失抑制的关键下游效应因子。在cSCC和成纤维细胞中，TOPK敲低降低了IL19的表达和分泌。IL19促进了cSCC的生长，并激活了PI3K/AKT、ERK和TOPK通路。此外，长期暴露于TGFβ可增加IL19表达并激活成纤维细胞，表现为αSMA和FAPα水平升高。 **结论：** 本研究证实TOPK是太阳紫外线诱导皮肤癌发生的关键调控因子，其作用部分通过调节IL19信号通路和成纤维细胞活化实现。靶向TOPK可能为NMSC的预防和治疗提供新策略。
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