Merkel cell carcinoma-derived exosome-shuttle miR-375 induces fibroblast polarization by inhibition of RBPJ and p53

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Antagomirs / pharmacology
  • Cancer-Associated Fibroblasts / metabolism
  • Cancer-Associated Fibroblasts / pathology
  • Carcinogenesis / genetics
  • Carcinoma, Merkel Cell / genetics*
  • Carcinoma, Merkel Cell / pathology
  • Cell Polarity / genetics
  • Chemokine CXCL2 / genetics
  • Exosomes / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / antagonists & inhibitors*
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics
  • Interleukin-1beta / genetics
  • MicroRNAs / genetics*
  • RNA-Seq
  • Signal Transduction / genetics
  • Single-Cell Analysis
  • Tumor Microenvironment / genetics
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / genetics


  • ACTA2 protein, human
  • Actins
  • Antagomirs
  • Chemokine CXCL2
  • IL1B protein, human
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • Interleukin-1beta
  • MIRN375 microRNA, human
  • MicroRNAs
  • RBPJ protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53