5-Fluorouracil (5-FU) resistance has always been a formidable obstacle in the adjuvant treatment of advanced colorectal cancer (CRC). In recent years, long non-coding RNAs have emerged as key regulators in various pathophysiological processes including 5-FU resistance. TRG is a postoperative pathological score of the chemotherapy effectiveness for CRC, of which TRG 0–1 is classified as chemotherapy sensitivity and TRG 3 as chemotherapy resistance. Here, RNA-seq combined with weighted gene correlation network analysis confirmed the close association of GAS6-AS1 with TRG. GAS6-AS1 expression was positively correlated with advanced clinicopathological features and poor prognosis in CRC. GAS6-AS1 increased the 50% inhibiting concentration of 5-FU, enhanced cell proliferation and accelerated G1/S transition, 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. Together, our findings elucidate that GAS6-AS1 directly binds to PCBP1, enhancing MCM3 expression and thereby promoting 5-FU resistance. GAS6-AS1 may serve as a robust biomarker and potential therapeutic target for combination therapy in CRC.

中文翻译：

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LncRNA GAS6-AS1 通过促进 PCBP1 与 MCM3 的结合，促进结直肠癌的 5-氟尿嘧啶耐药

5-氟尿嘧啶（5-FU）耐药一直是晚期结直肠癌（CRC）辅助治疗的巨大障碍。近年来，长链非编码RNA已成为包括5-FU耐药在内的各种病理生理过程的关键调节因子。 TRG是CRC化疗效果的术后病理评分，其中TRG 0~1为化疗敏感性，TRG 3为化疗耐药。在这里，RNA-seq结合加权基因相关网络分析证实了GAS6-AS1与TRG的密切关联。 GAS6-AS1表达与结直肠癌的晚期临床病理特征和不良预后呈正相关。无论有或没有 5-FU，GAS6-AS1 在体外和体内均可增加 5-FU 的 50% 抑制浓度，增强细胞增殖并加速 G1/S 转变。从机制上讲，GAS6-AS1 通过招募 PCBP1 来增强 MCM3 mRNA 的稳定性，从而增加 MCM3 的表达。此外，PCBP1和MCM3抵消了GAS6-AS1对5-FU耐药性的影响。值得注意的是，PDX 模型表明，将化疗药物与 GAS6-AS1 敲低相结合可在体内产生优异的结果。总之，我们的研究结果阐明 GAS6-AS1 直接与 PCBP1 结合，增强 MCM3 表达，从而促进 5-FU 耐药性。 GAS6-AS1可能作为结直肠癌联合治疗的稳健生物标志物和潜在治疗靶点。