Merkel cell carcinoma-derived exosome-shuttle miR-375 induces fibroblast polarization by inhibition of RBPJ and p53.
Actins
/ genetics
Antagomirs
/ pharmacology
Cancer-Associated Fibroblasts
/ metabolism
Carcinogenesis
/ genetics
Carcinoma, Merkel Cell
/ genetics
Cell Polarity
/ genetics
Chemokine CXCL2
/ genetics
Exosomes
/ genetics
Gene Expression Regulation, Neoplastic
/ genetics
Humans
Immunoglobulin J Recombination Signal Sequence-Binding Protein
/ antagonists & inhibitors
Interleukin-1beta
/ genetics
MicroRNAs
/ genetics
RNA-Seq
Signal Transduction
/ genetics
Single-Cell Analysis
Tumor Microenvironment
/ genetics
Tumor Suppressor Protein p53
/ antagonists & inhibitors
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
18
06
2020
accepted:
18
11
2020
revised:
02
11
2020
pubmed:
15
12
2020
medline:
31
7
2021
entrez:
14
12
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33311552
doi: 10.1038/s41388-020-01576-6
pii: 10.1038/s41388-020-01576-6
pmc: PMC7862059
doi:
Substances chimiques
ACTA2 protein, human
0
Actins
0
Antagomirs
0
Chemokine CXCL2
0
IL1B protein, human
0
Immunoglobulin J Recombination Signal Sequence-Binding Protein
0
Interleukin-1beta
0
MIRN375 microRNA, human
0
MicroRNAs
0
RBPJ protein, human
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
980-996Références
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