Abstract
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 in vitro and animal experiments in vivo 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 in vitro. More importantly, silencing LGR6 improved the chemoresistance of ovarian cancer cells to cisplatin in vivo. 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.
Highlights
Ovarian cancer is one of the most common gynecological malignancies, as well as one of the leading causes responsible for the cancer-related deaths in females.[1]
The correlation of LGR6 with clinicopathological features in ovarian cancer patients were further investigated, and the results showed that high expression of LGR6 positively correlated with histologic types, International Federation of Gynecology and Obstetrics (FIGO) stages, poor chemotherapeutic response, and poor progression in ovarian cancer patients (Figures 2D and 2E; Table S3)
Our results demonstrated that LGR6 was upregulated in ovarian cancer tissues, which positively correlated with shorter overall and progressionfree survival in ovarian cancer patients
Summary
Ovarian cancer is one of the most common gynecological malignancies, as well as one of the leading causes responsible for the cancer-related deaths in females.[1]. Oncolytics Vol 14 September 2019 a 2019 The Authors. Www.moleculartherapy.org of cancer.[12,13,14] Likewise, Wnt/b-catenin signaling has been reported to be required for CSCs in ovarian cancer. Chen et al.[15] has found that STAT3 was found to be hyperactivated in ovarian cancer spheroids, where activity of Wnt/b-catenin was indispensable for STAT3-induced or maintained stemness in ovarian cancer cells; Mariya and colleagues[16] have reported that MMP10 promoted stemness and chemotherapeutic resistance of ovarian cancer stem-like cells by activating Wnt/b-catenin signaling. Further elucidating the mechanisms responsible for constitutive activation of Wnt signaling in ovarian cancer is of paramount importance
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