Hypoxia‐induced miR‐210‐3p expression in lung adenocarcinoma potentiates tumor development by regulating CCL2 mediated monocyte infiltration

Autor: Leena Arora, Debarun Patra, Soumyajit Roy, Sidhanta Nanda, Navneet Singh, Anita K. Verma, Anuradha Chakraborti, Suman Dasgupta, Durba Pal
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Molecular Oncology, Vol 18, Iss 5, Pp 1278-1300 (2024)
Druh dokumentu: article
ISSN: 1878-0261
1574-7891
DOI: 10.1002/1878-0261.13260
Popis: In most cancers, tumor hypoxia downregulates the expression of C‐C motif chemokine 2 (CCL2), and this downregulation has been implicated in monocyte infiltration and tumor progression; however, the molecular mechanism is not yet clear. We compared noncancerous and lung‐adenocarcinoma human samples for hypoxia‐inducible factor 1‐alpha (HIF‐1A), microRNA‐210‐3p (mir‐210‐3p), and CCL2 levels. Mechanistic studies were performed on lung adenocarcinoma cell lines and 3D tumor spheroids to understand the role of hypoxia‐induced miR‐210‐3p in the regulation of CCL2 expression and macrophage polarization. HIF‐1Α stabilization increases miR‐210‐3p levels in lung adenocarcinoma and impairs monocyte infiltration by inhibiting CCL2 expression. Mechanistically, miR‐210‐3p directly binds to the 3′untranslated region (UTR) of CCL2 mRNA and silences it. Suppressing miR‐210‐3p substantially downregulates the effect of hypoxia on CCL2 expression. Monocyte migration is significantly hampered in miR‐210‐3p mimic‐transfected HIF‐1A silenced cancer cells. In contrast, inhibition of miR‐210‐3p in HIF‐1A‐overexpressed cells markedly restored monocyte migration, highlighting a direct link between the miR‐210‐3p level and tumor monocyte burden. Moreover, miR‐210‐3p inhibition in 3D tumor spheroids promotes monocyte recruitment and skewing towards an antitumor M1 phenotype. Anti‐hsa‐miR‐210‐3p‐locked nucleic acid (LNA) delivery in a lung tumor xenograft zebrafish model caused tumor regression, suggesting that miR‐210‐3p could be a promising target for immunomodulatory therapeutic strategies against lung adenocarcinoma.
Databáze: Directory of Open Access Journals
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