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Hypoxic Melanoma Cells Deliver microRNAs to Dendritic Cells and Cytotoxic T Lymphocytes through Connexin-43 Channels

Authors
  • Tittarelli, Andrés1
  • Navarrete, Mariela2, 3
  • Lizana, Marcelo2
  • Hofmann-Vega, Francisca2
  • Salazar-Onfray, Flavio2, 3
  • 1 Programa Institucional de Fomento a la Investigación, Desarrollo e Innovación (PIDi), Universidad Tecnológica Metropolitana (UTEM), Santiago 8940577, Chile
  • 2 (F.S.-O.)
  • 3 Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
Type
Published Article
Journal
International Journal of Molecular Sciences
Publisher
MDPI AG
Publication Date
Oct 13, 2020
Volume
21
Issue
20
Identifiers
DOI: 10.3390/ijms21207567
PMID: 33066331
PMCID: PMC7589225
Source
PubMed Central
Keywords
License
Green

Abstract

Alterations in microRNA (miRNA) profiles, induced by tumor microenvironment stressors, like hypoxia, allow cancer cells to acquire immune-resistance phenotypes. Indeed, hypoxia-induced miRNAs have been implicated in cancer progression through numerous cancer cell non-autonomous mechanisms, including the direct transfer of hypoxia-responsive miRNA from cancer to immune cells via extracellular vesicles. Connexin-43 (Cx43)-constituted gap junctions (GJs) have also been involved in miRNA intercellular mobilization, in other biological processes. In this report, we aimed to evaluate the involvement of Cx43-GJs in the shift of miRNAs induced by hypoxia, from hypoxic melanoma cells to dendritic cells and melanoma-specific cytotoxic T lymphocytes (CTLs). Using qRT-PCR arrays, we identified that miR-192-5p was strongly induced in hypoxic melanoma cells. Immune cells acquired this miRNA after co-culture with hypoxic melanoma cells. The transfer of miR-192-5p was inhibited when hypoxic melanoma cells expressed a dominant negative Cx43 mutant or when Cx43 expression was silenced using specific short-hairpin RNAs. Interestingly, miR-192-5p levels on CTLs after co-culture with hypoxic melanoma cells were inversely correlated with the cytotoxic activity of T cells and with ZEB2 mRNA expression, a validated immune-related target of miR-192-5p, which is also observed in vivo. Altogether, our data suggest that hypoxic melanoma cells may suppress CTLs cytotoxic activity by transferring hypoxia-induced miR-192-5p through a Cx43-GJs driven mechanism, constituting a resistance strategy for immunological tumor escape.

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