LINC00665/miR-379-5p/GRP78 regulates cisplatin sensitivity in gastric cancer by modulating endoplasmic reticulum stress.

Acquired resistance to cisplatin (DDP)-based chemotherapy greatly hinders the treatment of gastric cancer (GC). LINC00665 serves as an oncogene in GC. Hence, the current study was designed to investigate the regulatory effects of LINC00665 on DDP-resistance of GC. LINC00665 and miR-379-5p expression levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and Glucose regulated protein 78 (GRP78) protein level was measured by western blot assay. Interactions between LINC00665 and miR-379-5p or between miR-379-5p and GRP78 were verified by dual luciferase reporter assay. Cell counting kit 8 (CCK-8) assay and flow cytometry assay respectively determine the proliferative ability and apoptosis of GC cells. Western blot analysis was also performed to detect the protein levels of C/EBP-homologous protein (CHOP), X box binding protein (XBP1) and apoptosis-related proteins. In addition, GRP78 expression was evaluated by immunofluorescence. It was observed that the expression levels of LINC00665 and GRP78 were upregulated, and the expression level of miR-379-5p was downregulated in DDP-sensitive and DDP-resistant GC cell lines. What's more, GRP78 expression and the cell growth inhibition rates of DDP-sensitive and DDP-resistant GC cells had a negative correlation. Additionally, miR-379-5p was a target miRNA of LINC00665, and GRP78 was a target mRNA of miR-379-5p. Functional studies revealed that knockdown of LINC00665 inhibited DDP-resistant GC cell proliferation, induced apoptosis as well as suppressed Endoplasmic reticulum (ER) stress. Mechanistically, knockdown of LINC00665 downregulated GRP78 expression by strengthening miR-379-5p. LINC00665 silencing could overcome DPP-resistance of GC cells by downregulating GRP78 via sponging miR-379-5p, indicating that LINC00665 might be a potential therapeutic target for DDP- resistant GC patients.