Ruan Xiaohong, Liu Aibin, Zhong Meigong, Wei Jihong, Zhang Weijian, Rong Yingrou, Liu Wanmin, Li Mingwei, Qing Xingrong, Chen Gaowen, Li Ronggang, Liao Yuehua, Liu Qiongru, Zhang Xin, Ren Dong, Wang Yifeng
Department of Obstetrics and Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, People's Republic of China.
Department of Gynecology, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen 529030, People's Republic of China.
Mol Ther Oncolytics. 2019 Apr 19;14:94-106. doi: 10.1016/j.omto.2019.04.002. eCollection 2019 Sep 27.
Leucine-rich-repeat-containing G protein-coupled receptors (LGRs) have been widely found to be implicated with development and progression in multiple cancer types. However, the clinical significance and biological functions of LGR6 in ovarian cancer remains unclear. In this study, LGR6 expression was mainly examined by immunohistochemistry. Functional assays and animal experiments were carried out to explore the effect of LGR6 on cancer stem cell (CSC) characteristics and chemotherapeutic responses in ovarian cancer cells. Luciferase assays and GSEA were used to discern the underlying mechanisms contributing to the roles of LGR6 in ovarian cancer. Here, we reported that LGR6 was upregulated in ovarian cancer, which positively correlated with poor chemotherapeutic response and progression survival in ovarian cancer patients. Loss-of-function assays showed that downregulating LGR6 abrogated the CSC-like phenotype and chemoresistance . More importantly, silencing LGR6 improved the chemoresistance of ovarian cancer cells to cisplatin . Mechanistic investigation further revealed that silencing LGR6 inhibited stemness and chemoresistance by repressing Wnt/β-catenin signaling. Collectively, our results uncover a novel mechanism contributing to LGR6-induced chemotherapeutic resistance in ovarian cancer, providing the evidence for LGR6 as a potential therapeutic target in ovarian cancer.
富含亮氨酸重复序列的G蛋白偶联受体（LGRs）已被广泛发现与多种癌症类型的发生发展有关。然而，LGR6在卵巢癌中的临床意义和生物学功能仍不清楚。在本研究中，主要通过免疫组织化学检测LGR6的表达。进行功能实验和动物实验以探讨LGR6对卵巢癌细胞中癌症干细胞（CSC）特性和化疗反应的影响。采用荧光素酶报告基因检测和基因集富集分析（GSEA）来识别LGR6在卵巢癌中发挥作用的潜在机制。在此，我们报道LGR6在卵巢癌中上调，这与卵巢癌患者化疗反应差和进展生存期短呈正相关。功能丧失实验表明，下调LGR6可消除CSC样表型和化疗耐药性。更重要的是，沉默LGR6可提高卵巢癌细胞对顺铂的化疗耐药性。机制研究进一步表明，沉默LGR6通过抑制Wnt/β-连环蛋白信号通路来抑制干性和化疗耐药性。总体而言，我们的研究结果揭示了LGR6诱导卵巢癌化疗耐药的新机制，为LGR6作为卵巢癌潜在治疗靶点提供了证据。
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