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Article

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

1
Programa Institucional de Fomento a la Investigación, Desarrollo e Innovación (PIDi), Universidad Tecnológica Metropolitana (UTEM), Santiago 8940577, Chile
2
Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
3
Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(20), 7567; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207567
Received: 16 September 2020 / Revised: 5 October 2020 / Accepted: 9 October 2020 / Published: 13 October 2020
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. View Full-Text
Keywords: connexin-43; gap junctions; microRNAs; melanoma; hypoxia; cytotoxic T lymphocytes; dendritic cells; miR-192; zeb2 connexin-43; gap junctions; microRNAs; melanoma; hypoxia; cytotoxic T lymphocytes; dendritic cells; miR-192; zeb2
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MDPI and ACS Style

Tittarelli, A.; Navarrete, M.; Lizana, M.; Hofmann-Vega, F.; Salazar-Onfray, F. Hypoxic Melanoma Cells Deliver microRNAs to Dendritic Cells and Cytotoxic T Lymphocytes through Connexin-43 Channels. Int. J. Mol. Sci. 2020, 21, 7567. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207567

AMA Style

Tittarelli A, Navarrete M, Lizana M, Hofmann-Vega F, Salazar-Onfray F. Hypoxic Melanoma Cells Deliver microRNAs to Dendritic Cells and Cytotoxic T Lymphocytes through Connexin-43 Channels. International Journal of Molecular Sciences. 2020; 21(20):7567. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207567

Chicago/Turabian Style

Tittarelli, Andrés, Mariela Navarrete, Marcelo Lizana, Francisca Hofmann-Vega, and Flavio Salazar-Onfray. 2020. "Hypoxic Melanoma Cells Deliver microRNAs to Dendritic Cells and Cytotoxic T Lymphocytes through Connexin-43 Channels" International Journal of Molecular Sciences 21, no. 20: 7567. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207567

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