目的  探讨高糖条件下U2小核核糖核蛋白相关SURP结构域包含蛋白（U2SURP）影响HCT116结肠癌细胞增殖的分子机制及二甲双胍的作用。方法  取临床结肠癌(CC)和糖尿病结肠癌(DCC)样本各8例；HCT116细胞高糖（33 mmol/L）条件下连续培养8 d，建立体外细胞高糖培养模型；链脲佐菌素（STZ，120 mg/kg）腹腔注射构建C57BL/6糖尿病小鼠，皮下接种MC38细胞建立糖尿病小鼠移植瘤模型。Western blotting 、Real-time PCR检测癌组织及HCT116细胞U2SURP表达水平；利用短发夹RNA（shRNA）敲减U2SURP，CCK-8和集落形成实验分析HCT116细胞的增殖水平，流式细胞术检测细胞周期变化。利用SRAMP和RBP suite数据库筛选U2SURP上游调控因子，在糖尿病小鼠移植瘤和细胞高糖模型中检测其表达水平；构建过表达胰岛素样生长因子2 mRNA结合蛋白3（IGF2BP3)和敲减U2SURP、IGF2BP3细胞系，检测其在高糖条件下对结肠癌细胞增殖的影响。利用HCT116细胞高糖培养模型，给予二甲双胍（0.0128 mol/L）处理，检测U2SURP及其上游因子的表达、细胞的增殖能力，并分析Akt/糖原合酶激酶-3β（GSK-3β）信号的调控作用。结果  糖尿病结肠癌组织和高糖培养的HCT116细胞U2SURP表达水平与对照组相比显著上调。高糖促进HCT116细胞增殖，敲减U2SURP则可抑制高糖对HCT116细胞的促增殖作用，并诱导细胞S期阻滞。筛选获得U2SURP上游调控因子IGF2BP3，其过表达可促进结肠癌细胞增殖，而敲减则可逆转高糖的促细胞增殖作用。二甲双胍可抑制高糖条件下U2SURP和IGF2BP3的上调，减弱细胞的增殖能力，降低Akt和GSK-3β的磷酸化水平。而抑制Akt可逆转高糖对U2SURP和IGF2BP3的上调作用，激活Akt则降低二甲双胍对U2SURP和IGF2BP3的抑制作用。结论  高糖条件下IGF2BP3通过m6A甲基化调节U2SURP、促进结肠癌细胞增殖；二甲双胍可通过抑制Akt信号通路，降低U2SURP和IGF2BP3的表达，进而抑制高糖对结肠癌细胞增殖的影响。

Objective  To investigate the molecular mechanism by which U2 snRNP-associated SURP domain containing protein (U2SURP) influences the proliferation of HCT116 colorectal cancer cells under high glucose conditions, and to examine the effect of metformin. Methods  Clinical samples from colorectal cancer (CC, n=8) and diabetes-CC(DCC, n=8)patients were collected. High-glucose cell model was established by culturing HCT116 cells with 33 mmol/L glucose for 8 days. Diabetic xenograft model was generated by inducing diabetes in C57BL/6 mice via streptozotocin (STZ) injection (120 mg/kg) and subsequent subcutaneous implantation of MC38 cells. U2SURP expression in tissues and cells were analyzed by Western blotting and Real-time PCR. The proliferation level of HCT116 cells was analyzed by CCK-8 and colony formation assays following U2SURP knockdown using short hairpin RNA(shRNA) and cell cycle progression was analyzed by flow cytometry. The upstream regulator of U2SURP was predicted by the SRAMP and RBP suite databases. The expression level of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) was examined in diabetic mouse xenograft models and high glucose-cultured cell models. Overexpression and knockdown cell lines were constructed to validate their effects on the proliferation of colon cancer cells under high glucose conditions. Using the high-glucose cultured HCT116 cell model, treatment with metformin (0.0128 mol/L), detected the expression of U2SURP and its upstream factor, cell proliferation capacity, and analyzed the regulatory role of the Akt/glycogen synthase kinase-3 (GSK-3β) signaling pathway. Results  U2SURP expression was significantly upregulated in both diabetic colorectal cancer tissues and high glucose-cultured HCT116 cells. High glucose promoted colorectal cancer cell proliferation, whereas knockdown of U2SURP inhibited this pro-proliferative effect and induced S-phase cell cycle arrest. We next screened IGF2BP3 as an upstream regulator of U2SURP and confirmedits overexpression promoted the proliferation of colon cancer cells, while its knockdown reversed the pro-proliferative effect of high glucose. Furthermore, metformin inhibited the upregulation of U2SURP and IGF2BP3 under high glucose conditions, weakened cell proliferation capacity, and reduced Akt and GSK-3β phosphorylation. Similarly, Akt inhibition reversed the upregulation of U2SURP and IGF2BP3 by high glucose, while Akt activation attenuated the suppressive effect of metformin on these genes. Conclusion  Under high glucose conditions, IGF2BP3 promotes colon cancer cell proliferation by regulating U2SURP in an m6A-dependent manner. Metformin mitigates this pro-proliferative effect by inhibiting the Akt signaling pathway, thereby reducing the expression of U2SURP and IGF2BP3.