Department of Translational Skin Cancer Research, University Hospital Essen, Essen, Germany.
German Cancer Consortium (DKTK), Essen, Germany.
Oncogene. 2021 Feb;40(5):980-996. doi: 10.1038/s41388-020-01576-6. Epub 2020 Dec 11.
Merkel cell carcinoma (MCC) is a highly invasive and metastatic skin cancer. While high expression of miR-375 is a characteristic of MCC, it seems not to contribute to the malignant phenotype of MCC cells. miR-375 enrichment in MCC-derived extracellular vesicles suggests its intercellular signaling function. Here, we demonstrate that horizontally transferred miR-375 causes fibroblast polarization toward cancer-associated fibroblasts (CAFs). The polarization is evidenced by phenotypic changes and induction of α-SMA, CXCL2, and IL-1β. Fibroblast polarization is inhibited by specific antagomirs and mimicked by experimental miR-375 expression. Mechanistically, miR-375 downregulates RBPJ and p53, two key players regulating fibroblast polarization. In clinical MCC samples, in situ hybridization located miR-375 in CAFs, which correlated with high α-SMA protein and low RBPJ and TP53 expression; single-cell RNAseq revealed a disparate fibroblast polarization negatively correlating with p53 pathway-related gene expression. Thus, the functional role of miR-375 in MCC is to generate a pro-tumorigenic microenvironment by inducing fibroblast polarization.
默克尔细胞癌（Merkel cell carcinoma，MCC）是一种高度侵袭性和转移性皮肤癌。虽然 miR-375 的高表达是 MCC 的特征，但它似乎对 MCC 细胞的恶性表型没有贡献。MCC 衍生的细胞外囊泡中 miR-375 的富集表明其具有细胞间信号传递功能。在这里，我们证明水平转移的 miR-375 导致成纤维细胞向癌相关成纤维细胞（cancer-associated fibroblasts，CAFs）极化。这种极化表型变化和α-SMA、CXCL2 和 IL-1β 的诱导证实了这一点。特异性反义寡核苷酸可以抑制成纤维细胞的极化，而实验性 miR-375 表达则可以模拟这种极化。在机制上，miR-375 下调了 RBPJ 和 p53，这两个调节成纤维细胞极化的关键因子。在临床 MCC 样本中，原位杂交将 miR-375 定位在 CAFs 中，这与高α-SMA 蛋白和低 RBPJ 和 TP53 表达相关；单细胞 RNAseq 揭示了一种不同的成纤维细胞极化，与 p53 通路相关基因表达呈负相关。因此，miR-375 在 MCC 中的功能作用是通过诱导成纤维细胞极化来产生促肿瘤微环境。
