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HIF-1α-activated long non-coding RNA KDM4A-AS1 promotes hepatocellular carcinoma progression via the miR-411-5p/KPNA2/AKT pathway.

ABSTRACT: Hepatocellular carcinoma (HCC) is the most common type of liver cancer with poor clinical outcomes. Long non-coding RNAs (lncRNAs) are extensively involved in the tumorigenesis and progression of HCC. However, more investigations should be carried out on novel lncRNAs and their effects on HCC. Here we identified a novel lncRNA KDM4A-AS1, which was aberrantly overexpressed in HCC tissues, associated with unfavorable clinical features and poor prognosis of patients. KDM4A-AS1 promoted HCC cell proliferation, migration, and invasion in vitro and contributed to HCC growth and lung metastasis in vivo. Mechanistically, KDM4A-AS1 was inversely modulated by miR-411-5p at the post-transcriptional level and facilitated Karyopherin α2 (KPNA2) expression by competitively binding miR-411-5p, thereby activating the AKT pathway. KPNA2 silencing, miR-411-5p overexpression, and AKT inhibitor (MK2206) consistently reversed KDM4A-AS1-enhanced proliferation, mobility, and EMT of HCC cells. KDM4A-AS1 was identified as a novel hypoxia-responsive gene and transactivated by hypoxia-inducible factor 1α (HIF-1α) in HCC cells. In turn, KDM4A-AS1 regulated HIF-1α expression through the KPNA2/AKT signaling pathway. Hence, this study revealed a novel hypoxia-responsive lncRNA, KDM4A-AS1, which contributed to HCC growth and metastasis via the KDM4A-AS1/KPNA2/HIF-1α signaling loop. Our findings provide a promising prognostic and therapeutic target for HCC.

SUBMITTER: Chen T

PROVIDER: S-EPMC8668937 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPeriodontitis is a prevalent oral inflammatory disease, which can cause periodontal ligament to a local hypoxia environment. However, the mechanism of hypoxia associated long non-coding RNAs (lncRNAs) involved in periodontitis is still largely unknown.MethodsMicroarray was performed to detect the expression patterns of lncRNAs in 3 pairs of gingival tissues from patients with periodontitis and healthy controls. The expression of lncRNA 01126 (LINC01126), miR-518a-5p and hypoxia-inducible factor-1α (HIF-1α) in periodontal tissues and in human periodontal ligament cells (hPDLCs) under hypoxia was measured by quantitative real-time polymerase chain reaction or western blot. Fluorescence in situ hybridization and cell fraction assay were performed to determine the subcellular localization of LINC01126 and miR-518a-5p. Overexpression or knockdown of LINC01126 or HIF-1α was used to confirm their biological roles in hPDLCs. MTT assays were performed to evaluate hPDLCs proliferation ability. Flow cytometry was used to detect apoptosis. ELISA was used to measure the expression levels of interleukin (IL)-1β, IL-6, IL-8 and TNF-α. Dual-luciferase reporter assays were performed to assess the binding of miR-518a-5p to LINC01126 and HIF-1α. RNA immunoprecipitation assay was used to identify whether LINC01126 and miR-518a-5p were significantly enriched in AGO-containing micro-ribonucleoprotein complexes.ResultsWe selected LINC01126, which was the most highly expressed lncRNA, to further verify its functions in periodontitis-induced hypoxia. The expression of LINC01126 was increased in periodontal tissues. In vitro experiment demonstrated that LINC01126 suppressed proliferation, promoted apoptosis and inflammation of hPDLCs under hypoxia via sponging miR-518a-5p. Moreover, we identified HIF-1α acted as a direct target of miR-518a-5p in hPDLCs and LINC01126 promoted periodontitis pathogenesis by regulating the miR-518a-5p/HIF-1α/MAPK pathway.ConclusionLINC01126 promotes periodontitis pathogenesis of hPDLCs via miR-518a-5p/HIF-1α/MAPK pathway, providing a possible clue for LINC01126-based periodontal therapeutic approaches.

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HIF-1α-activated long non-coding RNA KDM4A-AS1 promotes hepatocellular carcinoma progression via the miR-411-5p/KPNA2/AKT pathway.

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