Long noncoding RNA HAGLR sponges miR-338-3p to promote 5-Fu resistance in gastric cancer through targeting the LDHA-glycolysis pathway.

Gastric cancer (GC) is one of the most common human malignancies due to its invasiveness and metastasis. 5-Fu is a widely applied chemotherapeutic agent against GC. Although 5-Fu therapy has achieved improvements in GC treatment, a large fraction of patients developed drug resistance which significantly limited its clinical applications. Recent studies revealed pivotal roles of long non-coding RNAs (lncRNAs) in tumorigenesis and progressions of various tumors, including gastric cancer. However, the biological roles and molecular mechanisms of lncRNA HAGLR in gastric cancer remain unclear. Here we report HAGLR was upregulated in both gastric cancer tissues and cell lines. In addition, HAGLR was associated with poorly survival rate of GC patients. Blocking HAGLR inhibited GC cells proliferation and sensitized GC cells to 5-Fu. Bioinformatical analysis and luciferase assay demonstrated that HAGLR sponged miR-338-3p, which functions as a tumor suppressor in GC to downregulate it expressions. Moreover, from the established 5-Fu resistant gastric cancer cell line (HGC27 5-Fu R), we detected significantly elevated HAGLR, downregulated miR-338-3p, and glucose metabolism compared with parental HGC27 cells. We identified lactate dehydrogenase-A (LDHA), a glucose metabolism key enzyme, was the direct target of miR-338-3p in GC cells. Rescue experiments demonstrated that restoration of miR-338-3p in HAGLR-overexpressing HGC27 5-Fu R cells successfully overrode the HAGLR-promoted 5-Fu resistance through targeting LDHA. Taken together, this study revealed essential roles and molecular mechanisms for the HAGLR-mediated 5-Fu resistance in GC, contributing to development of new non-coding RNA-based therapeutic strategies against chemoresistant GC. This article is protected by copyright. All rights reserved.