Background: Recent evidence indicated that the lncRNA NKX2-1-AS1 (NKX2-1 antisense RNA 1) plays an important role in cancer progression and metastasis. However, the associated molecular mechanisms of NKX2-1-AS1 in GC are still unclear.
Methods: To determine the target of the study by bioinformatic analysis. NKX2-1-AS1 expression was measured in paired tumor and non-tumor tissues of 178 GC patients, by quantitative reverse transcription PCR. The in vitro and in vivo biological functions of NKX2-1-AS1 were examined by loss-of-function and gain-of-function experiments. The potential mechanisms of this competing endogenous RNA (ceRNA) were elucidated using dual-luciferase reporter assay, quantitative PCR, Western blot, and fluorescence in situ hybridization (FISH).
Results: NKX2-1-AS1 expression was upregulated in GC cell lines and tumor tissues, which was correlated with tumor progression and enhanced angiogenesis. Functionally, NKX2-1-AS1 overexpression promoted GC cell proliferation, metastasis, invasion, and angiogenesis, while NKX2-1-AS1 downregulation reversed these effects, both in vitro and in vivo. Bioinformatics analysis and dual-luciferase assay showed that the microRNA miR-145-5p is a direct target of NKX2-1-AS1, and that NKX2-1-AS1 acts as a ceRNA that regulates angiogenesis in the context of GC. The mechanistic study revealed that miR-145-5p specifically targets serpin family E member 1 (SERPINE1), and that the complex NKX2-1-AS1/miR-145-5p activates VEGFR2 signaling, via SERPINE1, to promote tumor proliferation and angiogenesis.
Conclusion: NKX2-1-AS1 upregulation is associated with tumor cell proliferation, increased angiogenesis, and poor prognosis in GC patients. NKX2-1-AS1 regulates SERPINE1 expression and VEGFR2 signaling by acting as a ceRNA for miR-145-5p.
