Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Fan, K; Spassova, I; Gravemeyer, J; Ritter, C; Horny, K; Lange, A; Gambichler, T; Ødum, N; Schrama, D; Schadendorf, D; Ugurel, S; Becker, JC.
Merkel cell carcinoma-derived exosome-shuttle miR-375 induces fibroblast polarization by inhibition of RBPJ and p53.
Oncogene. 2021; 40(5):980-996
Doi: 10.1038/s41388-020-01576-6
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PubMed
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- Führende Autor*innen der Med Uni Graz
- Becker Jürgen Christian
- Fan Kaiji
- Co-Autor*innen der Med Uni Graz
- Ritter Cathrin
- Schrama David
- Ugurel-Becker Selma
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- Abstract:
- 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.