Non-Small Cell Lung Cancer Downregulates miR-495 and miR-5688 Under Hypoxia to Maintain Interleukin-11 Expression

Background: Hypoxia is one of the hallmarks of cancer and is associated with poor prognosis. However, the molecular mechanism by which hypoxia promotes tumor progression remains unclear. MicroRNAs participate in almost all biological processes through posttranscriptional regulation of the expression of multiple genes. In thecurrent study, we found that two miRNAs, miR-495 and miR-5688, participate in NSCLC progression under hypoxia. Methods: The expression of miR-495 and miR-5688 in human tissue specimens was measured by quantitative RT-PCR (qRT-PCR). Colony formation, MTS, wound healing, and transwell assays and a xenograft model were used to evaluate the role of miR-495 and miR-5688 in tumor progression. Two algorithms, PicTar and TargetScan, were used to predict miRNA targets, and a dual-luciferase reporter assay was used to confirm the target. Findings: MiR-495 and miR-5688 were downregulated in NSCLC tissues compared with normal tissues. We determinedthat hypoxia led to the downregulation of miR-495 and miR-5688 in NSCLC cells. 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, IL-11. Furthermore, a series of rescue experiments demonstrated that miR-495 and miR-5688 executed their tumor suppressive role by repressing IL-11 expression. Interpretation: We identified two new players, miR-495 and miR-5688, that participate in NSCLC progression under hypoxia. Mechanistically, hypoxia downregulates miR-495 and miR-5688 in NSCLC to enhance IL-11 expression and tumor progression. Our study indicates that the miR-495/miR-5688/IL-11 axis may serve as a therapeutic target and potential biomarker for NSCLC. Funding Statement: This work was supported by the National Natural Science Foundation of China (Grant No. 81602026) and the Natural Science Foundation of Tianjin (Grant No. 18JCQNJC81600 and 18JCZDJC32600). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: All samples were obtained with informed consent, and the study was approved by the Ethics Committee of Tianjin Medical University Cancer Institute and Hospital. All mouse studies were approved by the Animal Ethics Committee of Tianjin Medical University.