Department of Gastrointestinal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China.
Eur Rev Med Pharmacol Sci. 2017 Oct;21(17):3857-3865.
In this study, we aimed to investigate the downstream effector of GLI2 in gastric cancer (GC) and their regulative effect on cancer stem cell (CSC) properties of GC.
Bioinformatic data mining was performed in TCGA-Stomach Adenocarcinoma (STAD), as well as in Kaplan-Meier plotter. Moderate-differentiated GC cell line SGC-7901 and poor-differentiated GC cell line MKN-45 were used as in-vitro model to investigate the regulative effect of GLI2 on PDGFRB expression. MKN-45 cells were further used to explore the effect of GLI2 shRNA or PDGFRB shRNA on CSC properties of the cells.
Bioinformatic results showed that GLI2 is usually upregulated in GC tissues than in normal tissues, and high GLI2 expression is associated with unfavorable first progression free survival (PFS) and also worse overall survival (OS) in patients with GC. PDGFRB is co-upregulated with GLI2 in GC and its promoter region contains a putative GLI2 binding site. The results of dual luciferase assay confirmed this binding site. Enforced GLI2 expression elevated PDGFRB expression at both mRNA and protein level. GLI2 or PDGFRB knockdown showed similar effect on reducing spheroid colony formation and on reducing the expression of CSC related genes, including CD44, Nanog, and Oct4 in MKN-45 cells.
High GLI2 or PDGFRB expression is associated with unfavorable survival in GC patients. GLI2 can induce PDGFRB expression in GC cells via directly binding to its promoter. In addition, the GLI2-PDGFRB axis might be an important signaling pathway modulating CSC properties of GC cells.
本研究旨在探讨 GLI2 在胃癌（GC）中的下游效应因子及其对 GC 肿瘤干细胞（CSC）特性的调节作用。
在 TCGA-胃腺癌（STAD）中进行生物信息学数据挖掘，并在 Kaplan-Meier plotter 中进行验证。使用中分化 GC 细胞系 SGC-7901 和低分化 GC 细胞系 MKN-45 作为体外模型，研究 GLI2 对 PDGFRB 表达的调节作用。进一步使用 MKN-45 细胞探索 GLI2 shRNA 或 PDGFRB shRNA 对细胞 CSC 特性的影响。
生物信息学结果显示，GLI2 在 GC 组织中通常高表达，高于正常组织，且高 GLI2 表达与 GC 患者不利的无进展生存期（PFS）和总体生存期（OS）相关。PDGFRB 在 GC 中与 GLI2 共同上调，其启动子区域包含一个假定的 GLI2 结合位点。双荧光素酶报告基因实验证实了该结合位点。过表达 GLI2 可上调 PDGFRB 的 mRNA 和蛋白表达。GLI2 或 PDGFRB 敲低对减少 MKN-45 细胞球体集落形成和降低 CSC 相关基因（包括 CD44、Nanog 和 Oct4）的表达具有相似的效果。
高 GLI2 或 PDGFRB 表达与 GC 患者不良预后相关。GLI2 可通过直接结合其启动子诱导 GC 细胞中 PDGFRB 的表达。此外，GLI2-PDGFRB 轴可能是调节 GC 细胞 CSC 特性的重要信号通路。
