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/b-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.

Aberrant DNA damage response (DDR) signaling is one of major reasons underlying chemotherapy failure in cancer, and understanding the mechanism underlying aberrant DDR signaling would aid in developing novel strategies for overcoming cancer chemoresistance. The present study demonstrated that the expression of the DDUP microprotein, encoded by the CTBP1-DT lncRNA, increased in chemotherapy non-response ovarian cancer cells and was inversely correlated to platinum-based chemotherapy response. Using a patient-derived human cancer cell model, we observed that the formation of DDUP foci, which is induced by DNA damage, played an important role in platinum-based chemotherapy resistance through dual RAD51C-mediated homologous recombination (HR) and proliferating cell nuclear antigen (PCNA)-mediated post-replication repair (PRR) mechanisms. These mechanisms are mediated via interactions with RAD18/RAD51C and RAD18/PCNA complexes at the sites of DNA damage and sustained RAD18-mediated DNA damage signaling. Notably, treatment with an ATR inhibitor disrupted the DDUP/RAD18 interaction and abolished the effect of DDUP on prolonged DNA damage signaling, which resulted in the hypersensitivity of ovarian cancer cells to platinum-based chemotherapy in vivo. Altogether, the study provides insights into DDUP-mediated aberrant DDR signaling in cancer chemoresistance and describes a potential novel therapeutic approach for the management of platinum-resistant ovarian cancer.