Center for Experimental Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China; Medical Innovation Center, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China.
Medical Innovation Center, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China.
Biochim Biophys Acta Mol Cell Res. 2024 Jun;1871(5):119744. doi: 10.1016/j.bbamcr.2024.119744. Epub 2024 May 1.
Lung squamous cell carcinoma (LUSC) is associated with high mortality and has limited therapeutic treatment options. Plasminogen activator urokinase (PLAU) plays important roles in tumor cell malignancy. However, the oncogenic role of PLAU in the progression of LUSC remains unknown. GATA-binding factor 6 (GATA6), a key regulator of lung development, inhibits LUSC cell proliferation and migration, but the underlying regulatory mechanism remains to be further explored. Moreover, the regulatory effect of GATA6 on PLAU expression has not been reported. The aim of this study was to identify the role of PLAU and the transcriptional inhibition mechanism of GATA6 on PLAU expression in LUSC.
To identify the potential target genes regulated by GATA6, differentially expressed genes (DEGs) obtained from GEO datasets analysis and RNA-seq experiment were subjected to Venn analysis and correlation heatmap analysis. The transcriptional regulatory effects of GATA6 on PLAU expression were detected by real-time PCR, immunoblotting, and dual-luciferase reporter assays. The oncogenic effects of PLAU on LUSC cell proliferation and migration were evaluated by EdU incorporation, Matrigel 3D culture and Transwell assays. PLAU expression was detected in tissue microarray of LUSC via immunohistochemistry (IHC) assay. To determine prognostic factors for prognosis of LUSC patients, the clinicopathological characteristics and PLAU expression were subjected to univariate Cox regression analysis.
PLAU overexpression promoted LUSC cell proliferation and migration. PLAU is overexpressed in LUSC tissues compared with normal tissues. Consistently, high PLAU expression, which acts as an independent risk factor, is associated with poor prognosis of LUSC patients. Furthermore, the expression of PLAU is transcriptionally regulated by GATA6.
In this work, it was revealed that PLAU is a novel oncogene for LUSC and a new molecular regulatory mechanism of GATA6 in LUSC was unveiled. Targeting the GATA6/PLAU pathway might help in the development of novel therapeutic treatment strategies for LUSC.
肺鳞状细胞癌（LUSC）与高死亡率相关，且治疗选择有限。尿激酶型纤溶酶原激活物（PLAU）在肿瘤细胞恶性转化中发挥重要作用。然而，PLAU 在 LUSC 进展中的致癌作用尚不清楚。GATA 结合因子 6（GATA6）是肺发育的关键调节因子，可抑制 LUSC 细胞增殖和迁移，但潜在的调控机制仍有待进一步探讨。此外，GATA6 对 PLAU 表达的调控作用尚未见报道。本研究旨在鉴定 PLAU 的作用以及 GATA6 对 LUSC 中 PLAU 表达的转录抑制机制。
为了鉴定 GATA6 调控的潜在靶基因，对 GEO 数据集分析和 RNA-seq 实验中获得的差异表达基因（DEGs）进行 Venn 分析和相关热图分析。通过实时 PCR、免疫印迹和双荧光素酶报告基因检测，检测 GATA6 对 PLAU 表达的转录调控作用。通过 EdU 掺入、Matrigel 3D 培养和 Transwell 分析评估 PLAU 对 LUSC 细胞增殖和迁移的致癌作用。通过免疫组织化学（IHC）检测组织微阵列中 LUSC 的 PLAU 表达。为了确定 LUSC 患者预后的预后因素，对临床病理特征和 PLAU 表达进行单因素 Cox 回归分析。
PLAU 过表达促进 LUSC 细胞增殖和迁移。PLAU 在 LUSC 组织中的表达高于正常组织。一致地，高 PLAU 表达作为独立危险因素与 LUSC 患者的不良预后相关。此外，PLAU 的表达受 GATA6 转录调控。
在这项工作中，揭示了 PLAU 是 LUSC 的一种新型癌基因，并揭示了 GATA6 在 LUSC 中的新分子调控机制。靶向 GATA6/PLAU 途径可能有助于开发 LUSC 的新型治疗策略。
