MicroRNA‑214 upregulates HIF‑1α and VEGF by targeting ING4 in lung cancer cells

Abstract

Previous reports have indicated a potential link between microrna (mir)-214 and hypoxia. in the present study, the biological functions and potential mechanisms of mir-214 were determined, as well as its correlation with HiF-1α signaling in non-small cell lung cancer (nSclc) cells. Quantitative polymerase chain reaction revealed that mir-214 expression was upregulated in lung cancer tissues compared with adjacent normal tissues. mir-214 mimics were transfected into a549 cells, and MTT, colony formation, invasion and wound healing assays were performed. it was demonstrated that mir-214 mimic transfection promoted the invasion, proliferation and migration of a549 cells. Furthermore, mir-214 inhibitor transfection decreased H1299 cell invasion, proliferation and migration. next, the association between mir-214 expression and the HiF-1α signaling cascade was examined. it was demonstrated that mir-214 mimics upregulated the expression of hypoxia-inducible factor (HiF)-1α, vascular endothelial growth factor (VeGF), adenylate kinase 3 and matrix metalloproteinase (MMP)2, whereas mir-214 inhibitor downregulated the expression of these factors. using prediction software, it was demonstrated that tumor suppressor inG4 was a target of mir-214. a luciferase reporter assay confirmed that ING4 was a direct target of miR-214. There was a negative correlation between inG4 and mir-214 expression in lung cancer tissues. in addition, inG4 sirna and plasmid was transfected into cells in order to validate its effect on HiF-1α, MMP2 and VeGF expression. inG4 overexpression downregulated HiF-1α and its targets MMP2 and VeGF, while inG4 sirna upregulated HiF-1α, MMP2 and VeGF. in conclusion, it was demonstrated that mir-214 targeted inG4 in lung cancer cells, and upregulated the HiF-1α cascade, leading to MMP2 and VeGF upregulation. This approach may help to clarify the role of mirna in non-small lung cancer and may be a new therapeutic target for non-small lung cancer.

The Biological and Clinical Relevance of Inhibitor of Growth (ING) Genes in Non-Small Cell Lung Cancer

“…MiR-214 was up-regulated in lung cancer tissues as compared to adjacent non-cancerous tissue. Similarly to miR-761, it was confirmed that ING4 is a direct target of miR-214 as well, according to this study [46]. MiR-214 acted pro-carcinogenic, its over-expression leading to an up-regulation of the HIF-1alpha cascade and VEGF up-regulation in NSCLC cell lines.…”

“…Tumor-suppressive properties of ING4 are thus reversed by the cancer-promoting miR-761. A further study on a miRNA, miR-214, was carried out with the aim to enlighten a possible connection to ING4 gene function [46]. MiR-214 was up-regulated in lung cancer tissues as compared to adjacent non-cancerous tissue.…”

The interplay between HIF-1α and noncoding RNAs in cancer

“…In addition to the basic interaction between miRNAs and the 3'-UTR of HIF-1α, miRNA-mediated transcriptional regulation of HIF-1α expression is a common mechanism in cancer progression. MiR-214 upregulates HIF-1α and VEGFA with the suppression of ING4 to promote the invasion, proliferation and migration of non-small-cell lung cancer cells [132], and a possible mechanism is that ING4, which is recruited by egl-9 family hypoxia-inducible factor 1 (EGLN1), unexpectedly miR-338-3p hepatocellular cancer inhibits viability and induces apoptosis, enhances the sensitivity to sorafenib post-transcriptional regulation [102] miR-138 ovarian cancer inhibits migration and invasion post-transcriptional regulation [103] miR-576-3p glioma inhibits migration and proangiogenic abilities post-transcriptional regulation [104] miR-18a-5p lung cancer promotes radiosensitivity post-transcriptional regulation [105] miR-3662 hepatocellular cancer inhibits warburg effect and growth post-transcriptional regulation [106] miR-143-5p gallbladder cancer inhibits EMT, proliferation, migration and invasion post-transcriptional regulation [107] miR-143 cervical cancer inhibits proliferation, promotes apoptosis post-transcriptional regulation [108] miR-106a/b breast cancer inhibits stem-like cell specific, self-renewal and sphere-forming phenotype post-transcriptional regulation [109] miR-199a-5p melanoma inhibits proliferation, induces arrest post-transcriptional regulation [110] miR-20b osteosarcoma inhibits proliferation and invasion post-transcriptional regulation [111] miR-18b melanoma inhibits proliferation, induces arrest, inhibits the glycolysis post-transcriptional regulation [112] miR-622 lung cancer inhibits migration and invasion post-transcriptional regulation [113] miR-33a melanoma inhibits proliferation, invasion and metastasis post-transcriptional regulation [114] miR-338 nasopharyngeal carcinoma inhibits migration and proliferation post-transcriptional regulation [115] miR-20b hepatocellular cancer inhibits proliferation, inhibits apoptosis post-transcriptional regulation [116] miR-199a-5p multiple myeloma inhibits migration, promotes adhesion, inhibits endothelial cells migration post-transcriptional regulation [117] miR-199b prostate cancer inhibits growth, promotes death post-transcriptional regulation [118] miR-199a hepatocellular cancer inhibits proliferation post-transcriptional regulation [119] miR-138 renal cancer promotes apoptosis, inhibits migration post-transcriptional regulation [120] miR-22 colon cancer inhibits endothelial cell growth and invasion post-transcriptional ...…”

“…gallbladder cancer promotes migration, invasion and EMT post-transcriptional regulation [122] lncRNA PVT1 lung cancer promotes viability and proliferation post-transcriptional regulation [123] lncRNA HOTAIR renal cancer promotes proliferation, migration and EMT, inhibits apoptosis post-transcriptional regulation [124] lncRNA ROR hepatocellular cancer promotes viability post-transcriptional regulation [125] lncRNA NEAT1 osteosarcoma promotes proliferation and invasion post-transcriptional regulation [126] lncRNA UCA1 acute myelocytic leukemia promotes glycolysis and chemoresistance post-transcriptional regulation [127] lncRNA PVT1 gastric cancer promotes proliferation and invasion post-transcriptional regulation [128] lncRNA DANCR nasopharyngeal carcinoma promotes invasion and metastasis post-transcriptional activation via ILF3/ ILF2 [129] circPIP5K1A lung cancer promotes proliferation and metastasis post-transcriptional regulation [130] circRNA_0046600 hepatocellular carcinoma promotes migration post-transcriptional regulation [131] miR-214 lung cancer promotes invasion, proliferation and migration transcriptional activation via ING4 [132] miR-206 lung cancer inhibits proliferation and angiogenesis, promotes apoptosis transcriptional inhibition via 14-3-3ζ/STAT3 axis [133] miR-675-5p glioma promotes angiogenesis stabilize the mRNA via HuR [134] lncRNA CPS1-IT1 hepatocellular cancer inhibits EMT, proliferation, migration and invasion transcriptional inhibition via Hsp90 [135] lncRNA PVT1 gastric cancer promotes survival, inhibits apoptosis transcriptional activation via mTOR [136] has no effect on HIF-1α degeneration but acts as an adapter protein to recruit transcriptional repressors to regulate HIF activity [157]. MiR-206 can attenuate the growth and angiogenesis of non-small-cell lung cancer cells through the 14-3-3z/STAT3/HIF-1α/VEGF pathway.…”

Dried Blood Specimens as an Alternative Specimen for Immune Response Monitoring During HIV Infection: A Proof of Concept and Simple Method in a Pediatric Cohort

“…HIF-1α accumulates in the presence of HIV infection, since HIV-1 Vpr protein activates the oxidative stress pathway required for HIF-1α expression, explaining the high HIF-1α levels in HIV-infected individuals ( 38 ). Alternative molecular mechanisms for HIF-1α overexpression in HEU vs. UU should be elucidated, as occurs in other clinical contexts such as lung cancer ( 49 ).…”