Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Province, People's Republic of China.
Br J Cancer. 2022 Oct;127(7):1239-1253. doi: 10.1038/s41416-022-01902-7. Epub 2022 Jul 21.
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.
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.
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.
Our study identifies the LHX2-FGF1-FGFR axis plays a key role in NPC progression and provides a potential target for NPC therapy.
远处转移和复发仍然是鼻咽癌（NPC）治疗的主要障碍。然而，NPC 生长和转移的分子机制尚未完全阐明。
使用定量逆转录聚合酶链反应、western blot 和免疫组织化学检测 NPC 细胞系和 NPC 组织中的 LHX2 表达。使用过表达或沉默 LHX2 的 NPC 细胞进行 CCK-8 测定、集落形成测定、EdU 测定、划痕愈合和侵袭测定。进行体内实验涉及异种移植肿瘤模型和肺转移模型。应用基因集富集分析（GSEA）、ELISA 测定、western blot、染色质免疫沉淀（ChIP）测定和荧光素酶报告基因测定来研究下游靶机制。
LIM 同源结构域转录因子 2（LHX2）在 NPC 组织和细胞系中上调。LHX2 的升高与 NPC 患者的不良预后密切相关。异位 LHX2 过表达可显著促进 NPC 细胞在体外和体内的生长、迁移和侵袭。在机制上，LHX2 转录增加了成纤维细胞生长因子 1（FGF1）的表达，进而以自分泌和旁分泌方式激活 STAT3（信号转导和转录激活因子 3）、ERK1/2（细胞外调节蛋白激酶 1/2）和 AKT 信号通路的磷酸化，从而促进 NPC 的生长和转移。用 siRNA 或 FGFR 抑制剂抑制 FGF1 可阻断 LHX2 诱导的鼻咽癌细胞生长、迁移和侵袭。
我们的研究确定了 LHX2-FGF1-FGFR 轴在 NPC 进展中起关键作用，并为 NPC 治疗提供了一个潜在的靶点。
