LHX2 facilitates the progression of nasopharyngeal carcinoma via activation of the FGF1/FGFR axis.

BACKGROUND: Distant metastasis and recurrence remain the main obstacle to nasopharyngeal carcinoma (NPC) treatment. However, the molecular mechanisms underlying NPC growth and metastasis are poorly understood. METHODS: LHX2 expression was examined in NPC cell lines and NPC tissues using quantitative reverse transcription-polymerase chain reaction, western blotting and Immunohistochemistry assay. NPC cells overexpressing or silencing LHX2 were used to perform CCK-8 assay, colony-formation assay, EdU assay, wound-healing and invasion assays in vitro. Xenograft tumour models and lung metastasis models were involved for the in vivo assays. The Gene Set Enrichment Analysis (GSEA), ELISA assay, western blot, chromatin immunoprecipitation (ChIP) assay and Luciferase reporter assay were applied for the downstream target mechanism investigation. RESULTS: LIM-homeodomain transcription factor 2 (LHX2) was upregulated in NPC tissues and cell lines. Elevated LHX2 was closely associated with poor survival in NPC patients. Ectopic LHX2 overexpression dramatically promoted the growth, migration and invasion of NPC cells both in vitro and in vivo. Mechanistically, LHX2 transcriptionally increased the fibroblast growth factor 1 (FGF1) expression, which in turn activated the phosphorylation of STAT3 (signal transducer and activator of transcription 3), ERK1/2 (extracellular regulated protein kinases 1/2) and AKT signalling pathways in an autocrine and paracrine manner, thereby promoting the growth and metastasis of NPC. Inhibition of FGF1 with siRNA or FGFR inhibitor blocked LHX2-induced nasopharyngeal carcinoma cell growth, migration and invasion. CONCLUSIONS: Our study identifies the LHX2-FGF1-FGFR axis plays a key role in NPC progression and provides a potential target for NPC therapy.

Regulatory coupling between long noncoding RNAs and senescence in irradiated microglia.

BACKGROUND: Microglia have been implicated in the pathogenesis of radiation-induced brain injury (RIBI), which severely influences the quality of life during long-term survival. Recently, irradiated microglia were speculated to present an aging-like phenotype. Long noncoding RNAs (lncRNAs) have been recognized to regulate a wide spectrum of biological processes, including senescence; however, their potential role in irradiated microglia remains largely uncharacterized. METHODS: We used bioinformatics and experimental methods to identify and analyze the senescence phenotype of irradiated microglia. Western blotting, enzyme-linked immunosorbent assays, immunofluorescence, and quantitative real-time reverse transcription-polymerase chain reaction were performed to clarify the relationship between the radiation-induced differentially expressed lncRNAs (RILs) and the distinctive molecular features of senescence in irradiated microglia. RESULTS: We found that the senescence of microglia could be induced using ionizing radiation (IR). A mutual regulation mode existed between RILs and three main features of the senescence phenotype in irradiated microglia: inflammation, the DNA damage response (DDR), and metabolism. Specifically, for inflammation, the expression of two selected RILs (ENSMUST00000190863 and ENSMUST00000130679) was dependent on the major inflammatory signaling pathways of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK). The two RILs modulated the activation of NF-κB/MAPK signaling and subsequent inflammatory cytokine secretion. For the DDR, differential severity of DNA damage altered the expression profiles of RILs. The selected RIL, ENSMUST00000130679, promoted the DDR. For metabolism, blockade of sterol regulatory element-binding protein-mediated lipogenesis attenuated the fold-change of several RILs induced by IR. CONCLUSIONS: Our findings revealed that certain RILs interacted with senescence in irradiated microglia. RILs actively participated in the regulation of senescence features, suggesting that RILs could be promising intervention targets to treat RIBI.