Abstract | BACKGROUND:
Hypoxia is a hallmark of cancer and is associated with poor prognosis. However, the molecular mechanism by which hypoxia promotes tumor progression remains unclear. MicroRNAs dysregulation has been shown to play a critical role in the tumor and tumor microenvironment. Here, we investigated the roles of miR-495 and miR-5688 in human non-small cell lung cancer (NSCLC) and their underlying mechanism. METHODS: The expression levels of miR-495 and miR-5688 in human NSCLC tissue specimens were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Deferoxamine (DFO) was used to determine whether the regulation of miR-495 and miR-5688 under hypoxia was dependent on hypoxia-inducible factor 1-alpha (HIF-1α). Furthermore, the functions of miR-495 and miR-5688 in tumor progression were evaluated using colony formation, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), wound healing, transwell assays, and xenograft model. Two algorithms, PicTAR and Targetscan, were used to predict the target gene of these two miRNAs, and dual- luciferase reporter assay was conducted to confirm the target. The unpaired two-tailed t test, Pearson correlation analysis, and Fisher's exact probability test were performed for statistical analyses. RESULTS: Two miRNAs, miR-495 and miR-5688, were found to participate in NSCLC progression under hypoxia. They were down-regulated in NSCLC tissues compared with normal tissues. We determined that hypoxia led to the down-regulation of miR-495 and miR-5688 in NSCLC cells, which was independent of HIF-1α and cellular metabolic energy. In addition, miR-495 and miR-5688 suppressed cell proliferation, migration, and invasion in vitro. The NSCLC xenograft model showed that miR-495 and miR-5688 inhibited tumor formation in vivo. Interestingly, we found that miR-495 and miR-5688 had the same target, interleukin-11 (IL-11). Recombinant human IL-11 counteracted the effects of miR-495 and miR-5688 on NSCLC cells, suggesting that miR-495 and miR-5688 executed their tumor suppressive role by repressing IL-11 expression. CONCLUSION: We found that hypoxia down-regulated the expression levels of miR-495 and miR-5688 in NSCLC to enhance IL-11 expression and tumor progression, indicating that the miR-495/miR-5688/IL-11 axis may serve as a therapeutic target and potential biomarker for NSCLC.
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Authors | Meng Zhao, Jiao Chang, Ran Liu, Yahui Liu, Jin Qi, Yanhui Wang, Xinwei Zhang, Lu Qiao, Yu Jin, Haohua An, Li Ren |
Journal | Cancer communications (London, England)
(Cancer Commun (Lond))
Vol. 40
Issue 9
Pg. 435-452
(09 2020)
ISSN: 2523-3548 [Electronic] United States |
PMID | 32720740
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2020 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center. |
Chemical References |
- IL11 protein, human
- Interleukin-11
- MIRN495 microRNA, human
- MIRN5688 microRNA, human
- MicroRNAs
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Topics |
- Carcinoma, Non-Small-Cell Lung
(genetics)
- Cell Movement
- Female
- Humans
- Hypoxia
- Interleukin-11
(genetics)
- Lung Neoplasms
(genetics)
- Male
- MicroRNAs
(genetics)
- Middle Aged
- Neoplasm Invasiveness
- Tumor Microenvironment
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