Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang 110122, Liaoning province, China; College of Life Engineering, Shenyang Institute of Technology, Fushun 113122, Liaoning province, China.
Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang 110122, Liaoning province, China.
Gynecol Oncol. 2020 Dec;159(3):839-849. doi: 10.1016/j.ygyno.2020.09.020. Epub 2020 Sep 24.
High-grade serous ovarian cancer (HGSOC) is lethal mainly due to extensive metastasis. Cancer cell stem-like properties are responsible for HGSOC metastasis. LGR4, a G-protein-coupled receptor, is involved in the maintenance of stem cell self-renewal and activity in some human organs.
TCGA and CCLE databases were interrogated for gene mRNA in ovarian cancer tissues and cell lines. Gain and loss of functions of LGR4, ELF3, FZD5 and WNT7B were performed to identify their roles in ovarian cancer cell epithelial phenotype and stem-like properties. In vivo experiments were performed to observe the effect of LGR4 on ovarian cancer cell growth and peritoneal seeding. The binding of ELF3 to LGR4 gene promoter was investigated by dual-luciferase reporter assays and ChIP.
LGR4 was shown to be overexpressed in HGSOCs and maintain the epithelial phenotype of HGSOC cells. LGR4 knockdown suppressed POU5F1, SOX2, PROM1 (CD133) and ALDH1A2 expression. Furthermore, LGR4 knockdown reduced CD133 and ALDH subpopulations and impaired tumorisphere formation. To the contrary, LGR4 overexpression enhanced POU5F1 and SOX2 expression and tumorisphere formation capacity. LGR4 knockdown inhibited HGSOC cell growth and peritoneal seeding in xenograft models. Mechanistically, LGR4 and ELF3, an epithelium-specific transcription factor, formed a reciprocal regulatory loop, which was positively modulated by WNT7B/FZD5 ligand-receptor pair. Consistently, knockdown of ELF3, WNT7B, and FZD5, respectively, disrupted HGSOC cell epithelial phenotype and stem-like properties.
Together, these data demonstrate that WNT7B/FZD5-LGR4/ELF3 axis maintains HGSOC cell epithelial phenotype and stem-like traits; targeting this axis may prevent HGSOC metastasis.
高级别浆液性卵巢癌（HGSOC）主要因其广泛转移而致命。癌细胞的干性特征是导致 HGSOC 转移的原因。LGR4 是一种 G 蛋白偶联受体，参与维持某些人体器官中的干细胞自我更新和活性。
通过 TCGA 和 CCLE 数据库分析卵巢癌组织和细胞系中的基因 mRNA。进行 LGR4、ELF3、FZD5 和 WNT7B 的功能获得和缺失实验，以鉴定它们在卵巢癌细胞上皮表型和干性特征中的作用。进行体内实验观察 LGR4 对卵巢癌细胞生长和腹膜种植的影响。通过双荧光素酶报告基因检测和 ChIP 实验研究 ELF3 与 LGR4 基因启动子的结合。
LGR4 在 HGSOC 中过度表达，并维持 HGSOC 细胞的上皮表型。LGR4 敲低抑制 POU5F1、SOX2、PROM1（CD133）和 ALDH1A2 的表达。此外，LGR4 敲低减少了 CD133 和 ALDH 亚群，并损害了肿瘤球体的形成。相反，LGR4 过表达增强了 POU5F1 和 SOX2 的表达和肿瘤球体形成能力。LGR4 敲低抑制了异种移植模型中的 HGSOC 细胞生长和腹膜种植。从机制上讲，LGR4 和 ELF3（一种上皮特异性转录因子）形成了一个相互调节的循环，该循环受到 WNT7B/FZD5 配体-受体对的正调节。一致地，ELF3、WNT7B 和 FZD5 的敲低分别破坏了 HGSOC 细胞的上皮表型和干性特征。
综上所述，这些数据表明 WNT7B/FZD5-LGR4/ELF3 轴维持了 HGSOC 细胞的上皮表型和干性特征；靶向该轴可能预防 HGSOC 转移。
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