Chen I-Peng, Bender Marc, Spassova Ivelina, Henning Stefan, Kubat Linda, Fan Kaiji, Degenhardt Sarah, Mhamdi-Ghodbani Mouna, Sriram Ashwin, Volkmer Beate, Boukamp Petra, Becker Jürgen C, Greinert Rüdiger
Division of Molecular Cell Biology, Skin Cancer Center, Elbe Kliniken Stade-Buxtehude, 21614, Buxtehude, Germany.
Translational Skin Cancer Research, DKTK Partner Site Essen/Düsseldorf, West German Cancer Center, Dermatology, University Duisburg-Essen, 45117, Essen, Germany.
J Cancer Res Clin Oncol. 2020 Dec;146(12):3215-3231. doi: 10.1007/s00432-020-03358-9. Epub 2020 Aug 31.
UV exposure is the main risk factor for development of cutaneous squamous cell carcinoma (cSCC). While early detection greatly improves cSCC prognosis, locally advanced or metastatic cSCC has a severely impaired prognosis. Notably, the mechanisms of progression to metastatic cSCC are not well understood. We hypothesized that UV exposure of already transformed epithelial cSCC cells further induces changes which might be involved in the progression to metastatic cSCCs and that UV-inducible microRNAs (miRNAs) might play an important role.
Thus, we analyzed the impact of UV radiation of different quality (UVA, UVB, UVA + UVB) on the miRNA expression pattern in established cell lines generated from primary and metastatic cSCCs (Met-1, Met-4) using the NanoString nCounter platform.
This analysis revealed that the expression pattern of miRNAs depends on both the cell line used per se and on the quality of UV radiation. Comparison of UV-induced miRNAs in cSCC cell lines established from a primary tumor (Met-1) and the respective (un-irradiated) metastasis (Met-4) suggest that miR-7-5p, miR-29a-3p and miR-183-5p are involved in a UV-driven pathway of progression to metastasis. This notion is supported by the fact that these three miRNAs build up a network of 81 potential target genes involved e.g. in UVA/UVB-induced MAPK signaling and regulation of the epithelial-mesenchymal transition. As an example, PTEN, a target of UV-upregulated miRNAs (miR-29a-3p, miR-183-5p), could be shown to be down-regulated in response to UV radiation. We further identified CNOT8, the transcription complex subunit 8 of the CCR4-NOT complex, a deadenylase removing the poly(A) tail from miRNA-destabilized mRNAs, in the center of this network, targeted by all three miRNAs.
In summary, our results demonstrate that UV radiation induces an miRNA expression pattern in primary SCC cell line partly resembling those of metastatic cell line, thus suggesting that UV radiation impacts SCC progression beyond initiation.
紫外线暴露是皮肤鳞状细胞癌（cSCC）发生的主要危险因素。虽然早期检测可大大改善cSCC的预后，但局部晚期或转移性cSCC的预后严重受损。值得注意的是，转移性cSCC进展的机制尚未完全了解。我们推测，已转化的上皮cSCC细胞暴露于紫外线会进一步诱导可能参与转移性cSCC进展的变化，并且紫外线诱导的微小RNA（miRNA）可能起重要作用。
因此，我们使用NanoString nCounter平台分析了不同质量的紫外线辐射（UVA、UVB、UVA + UVB）对源自原发性和转移性cSCC（Met-1、Met-4）的已建立细胞系中miRNA表达模式的影响。
该分析表明，miRNA的表达模式既取决于所使用的细胞系本身，也取决于紫外线辐射的质量。对源自原发性肿瘤（Met-1）和相应（未照射）转移灶（Met-4）的cSCC细胞系中紫外线诱导的miRNA进行比较，表明miR-7-5p、miR-29a-3p和miR-183-5p参与了紫外线驱动的转移进展途径。这一观点得到以下事实的支持：这三种miRNA构建了一个由81个潜在靶基因组成的网络，这些靶基因参与例如UVA/UVB诱导的MAPK信号传导和上皮-间质转化的调节。例如，PTEN是紫外线上调的miRNA（miR-29a-3p、miR-183-5p）的靶标，已证明其在紫外线辐射后表达下调。我们进一步确定了CNOT8，它是CCR4-NOT复合物的转录复合体亚基8，是一种去腺苷酸化酶，可从miRNA不稳定的mRNA上去除多聚（A）尾，位于该网络的中心，被所有三种miRNA靶向。
总之，我们的结果表明，紫外线辐射在原发性SCC细胞系中诱导出一种部分类似于转移性细胞系的miRNA表达模式，从而表明紫外线辐射对SCC进展的影响超出了起始阶段。
