miR‐495 and miR‐5688 are down‐regulated in non‐small cell lung cancer under hypoxia to maintain interleukin‐11 expression

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.

YB1 regulates miR‐205/200b‐ZEB1 axis by inhibiting microRNA maturation in hepatocellular carcinoma

“…Data were presented as mean ± SD. *P < 0.05, **P < 0.001 Dysregulation of miRNAs have been reported to contribute to tumorigenesis and progression in various can-cers [15,17,18,61]. The miR-205 and miR-200 family members are known to suppress cell EMT and tumor metastasis by inhibiting ZEB1 and SIP expression in cancer cells [16].…”

DGUOK-AS1 acts as a tumor promoter through regulating miR-204-5p/IL-11 axis in breast cancer

“… 46 Moreover, IL-11 was found to exert oncogene effects in various cancers, such as colorectal cancer, 47 liver cancer, 48 and non-small cell lung cancer. 49 Recently, various studies indicated that IL-11 was upregulated in breast cancer tissues compared with normal tissues, and high expression of IL-11 was associated with poor prognosis in breast cancer patients. 50 , 51 Further study revealed that IL-11 plays a significant role in breast cancer progression, especially the well-documented capacity to promote breast cancer bone metastasis.…”

Emerging role of exosomes in cancer progression and tumor microenvironment remodeling

“…Recent experiments have shed light on the role of miRNAs in cancer. For example, hypoxic conditions enhance lung cancer progression by decreasing the expression of miRNA-495 and miRNA-5688 and subsequently increasing IL-11 levels [ 298 ]. Moreover, decreased expression of miRNA-100 and miRNA-125b paves the way for overexpression of IGF2 and subsequent cancer stem cell features in hepatocellular carcinoma [ 299 ].…”