LncRNA GAS6-AS1 contributes to 5-fluorouracil resistance in colorectal cancer by facilitating the binding of PCBP1 with MCM3

5-Fluorouracil (5-FU) resistance has always been a formidable obstacle in the adjuvant treatment of advanced colorectal cancer (CRC), significantly compromising the patients’ prognosis. In recent years, long non-coding RNAs (lncRNAs) have emerged as key regulators in various pathophysiological processes, particularly in cancers. However, the precise molecular mechanisms governed by these molecules in 5-FU resistance remain insufficiently elucidated. In this study, RNA-seq combined with weighted gene correlation network analysis (WGCNA) confirmed the close association of GAS6-AS1 with TRG grades. GAS6-AS1 expression was positively correlated with advanced clinicopathological features and poor prognosis in CRC. GAS6-AS1 increased the 50% inhibiting concentration (IC50) of 5-FU, enhanced cell proliferation, and accelerated G1/S transition in CRC cells, both with and without 5-FU, both in vitro and in vivo. Mechanistically, GAS6-AS1 enhanced the stability of MCM3 mRNA by recruiting PCBP1, consequently increasing MCM3 expression. Furthermore, PCBP1 and MCM3 counteracted the effects of GAS6-AS1 on 5-FU resistance. Notably, the PDX model indicated that combining chemotherapeutic drugs with GAS6-AS1 knockdown yielded superior outcomes in vivo. Taken together, our findings elucidate that GAS6-AS1 directly binds to PCBP1, enhancing MCM3 expression and thereby promoting 5-FU resistance in CRC. GAS6-AS1 may serve as a robust biomarker and potential therapeutic target for combination drug therapy in CRC.