Research Paper Volume 13, Issue 7 pp 10431—10449
miR-224 aggravates cancer-associated fibroblast-induced progression of non-small cell lung cancer by modulating a positive loop of the SIRT3/AMPK/mTOR/HIF-1α axis
- 1 Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang 441021, Hubei, China
Received: December 11, 2020 Accepted: February 8, 2021 Published: April 4, 2021https://doi.org/10.18632/aging.202803
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Copyright: © 2021 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Objectives: Cancer-associated fibroblast (CAF) is among the most important tumor-host microenvironment components by affecting tumor progression. This study explored the role of miR-224 in CAF-induced non-small cell lung cancer (NSCLC).
Materials and methods: A CAF-NSCLC cell co-culture model was established, and the miR-224 expression in CAF was detected by reverse transcription-polymerase chain reaction (RT-PCR). Gain- and loss- of experiments of miR-224 were implemented to verify the effects of CAF on NSCLC cell proliferation, invasion, and epithelial-mesenchymal transition (EMT), and endothelial cell (EC) angiogenesis. Overexpressing genetic or pharmacological interventions were performed to explore the potential mechanisms of Sirtuins 3/AMP-activated protein kinase/mammalian target of rapamycin/hypoxia-inducible factor-1α (SIRT3/AMPK/mTOR/HIF-1α).
Results: CAF enhanced the malignant phenotype of NSCLC cells and induced EC angiogenesis. miR-224 was significantly altered in CAFs. miR-224 up-regulation exacerbated NSCLC development mediated by CAFs, while miR-224 inhibition mostly reversed CAF-induced effects. Mechanistically, miR-224 targeted the 3’-untranslated regions (UTR) of SIRT3 mRNA, thereby inhibiting SIRT3/AMPK and activating mTOR/HIF-1α. Forced overexpression of SIRT3 up-regulated AMPK and inactivated mTOR/HIF-1α, while inhibiting HIF-1α markedly up-regulated SIRT3/AMPK and reduced mTOR phosphorylation. Interestingly, both Sirt1 overexpression and HIF-1α inhibition repressed miR-224 levels and miR-224-mediated promotive effects in NSCLC.
Conclusion: The miR-224-SIRT3/AMPK/mTOR/HIF-1α axis formed a positive feedback loop in modulating CAF-induced carcinogenic effects on NSCLC.