PUBLICATION
Hypoxia-induced miR-210-3p expression in lung adenocarcinoma potentiates tumor development by regulating CCL2-mediated monocyte infiltration
- Authors
- Arora, L., Patra, D., Roy, S., Nanda, S., Singh, N., Verma, A.K., Chakraborti, A., Dasgupta, S., Pal, D.
- ID
- ZDB-PUB-220607-1
- Date
- 2022
- Source
- Molecular Oncology 18(5): 1278-1300 (Journal)
- Registered Authors
- Keywords
- CCL2, HIF-1A, LUAD, miR-210-3p, monocyte infiltration
- MeSH Terms
-
- Monocytes*/metabolism
- Monocytes*/pathology
- Chemokine CCL2*/genetics
- Chemokine CCL2*/metabolism
- Zebrafish
- Animals
- Humans
- MicroRNAs*/genetics
- MicroRNAs*/metabolism
- Adenocarcinoma of Lung*/genetics
- Adenocarcinoma of Lung*/metabolism
- Adenocarcinoma of Lung*/pathology
- Cell Line, Tumor
- Lung Neoplasms*/genetics
- Lung Neoplasms*/metabolism
- Lung Neoplasms*/pathology
- Hypoxia-Inducible Factor 1, alpha Subunit*/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit*/metabolism
- Gene Expression Regulation, Neoplastic*
- Cell Hypoxia/genetics
- PubMed
- 35658112 Full text @ Mol. Oncol.
Citation
Arora, L., Patra, D., Roy, S., Nanda, S., Singh, N., Verma, A.K., Chakraborti, A., Dasgupta, S., Pal, D. (2022) Hypoxia-induced miR-210-3p expression in lung adenocarcinoma potentiates tumor development by regulating CCL2-mediated monocyte infiltration. Molecular Oncology. 18(5):1278-1300.
Abstract
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 yet not clear. We compared non-cancerous 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-1 A 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 miR-210-3p level and tumor monocyte burden. Moreover, miR-210-3p inhibition in 3D tumor spheroids promotes monocyte recruitment and skewing towards an anti-tumor 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping