Merkel cell carcinoma-derived exosome-shuttle miR-375 induces fibroblast polarization by inhibition of RBPJ and p53.
Merkel cell carcinoma-derived exosome-shuttle miR-375 induces fibroblast polarization by inhibition of RBPJ and p53.
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默克尔细胞癌来源的外体穿梭miR-375通过抑制RBPJ和P53诱导成纤维细胞极化。
DOI：
10.1038/s41388-020-01576-6
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发表时间：
2021-03
期刊：
影响因子：
8
通讯作者：
Becker JC
中科院分区：
文献类型：
--
作者：
Fan K;Spassova I;Gravemeyer J;Ritter C;Horny K;Lange A;Gambichler T;Ødum N;Schrama D;Schadendorf D;Ugurel S;Becker JC
默克尔细胞癌（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的一个特征，但它似乎并不有助于MCC细胞的恶性表型。miR-375在MCC衍生的细胞外囊泡中的富集表明其细胞间信号传导功能。在这里，我们证明了水平转移的miR-375导致成纤维细胞向癌症相关成纤维细胞（CAF）极化。表型变化和α-SMA、CXCL 2和IL-1β的诱导证明了极化。成纤维细胞极化被特异性miR-375抑制，并被实验性miR-375表达模拟。从机制上讲，miR-375下调RBPJ和p53，这两个关键参与者调节成纤维细胞极化。在临床MCC样本中，原位杂交在CAFs中定位了miR-375，其与高α-SMA蛋白和低RBPJ和TP 53表达相关;单细胞RNAseq显示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发生微环境。
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.
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影响因子：
3.6
作者：
Hudson, Jena;Duncavage, Eric;Tamburrino, Anna;Salerno, Paolo;Xi, Liqiang;Raffeld, Mark;Moley, Jeffrey;Chernock, Rebecca D.
通讯作者：
Chernock, Rebecca D.
影响因子：
8.8
作者：
Goruppi S;Procopio MG;Jo S;Clocchiatti A;Neel V;Dotto GP
通讯作者：
Dotto GP
DOI：
10.1186/s13058-016-0740-2
发表时间：
2016-08-11
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Bussard KM;Mutkus L;Stumpf K;Gomez-Manzano C;Marini FC
通讯作者：
Marini FC
影响因子：
5.2
作者：
Fan, Kaiji;Zebisch, Armin;Becker, Juergen C.
通讯作者：
Becker, Juergen C.
影响因子：
7.3
作者：
Khare, Drirh;Or, Reuven;Avni, Batia
通讯作者：
Avni, Batia