MTHFD2通过PI3K/AKT/c-Myc信号通路调控膀胱癌恶性增殖表型的机制研究

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a key enzyme in the one-carbon metabolism pathway and is involved in the regulation of tumor proliferation and energy homeostasis. MTHFD2 expressed higher in bladder cancer than in adjacent tissues, but whether MTHFD2 affects the malignant progression of bladder cancer and its mechanism is not clear. We found that over-expression of MTHFD2 promoted the proliferation of bladder cancer cells and knockout MTHFD2 inhibited proliferation. The oncogene c-Myc is involved in the regulation of cell division and transformation, and its protein stability is regulated by the PI3K/AKT pathway. High expression of MTHFD2 activated AKT and upregulated c-Myc, knockout MTHFD2 suppressed AKT activation and decreased c-Myc. Based on this, we aim to target by high expression and knockout of MTHFD2, reverting c-Myc expression, and in combination with PI3K/AKT signaling pathway inhibitor or agonist, to explore whether MTHFD2 can affect the malignant proliferation and metabolism of bladder cancer through PI3K/AKT/c-Myc signaling pathway, reveal the role of MTHFD2 in the diagnosis and treatment of bladder cancer, and provide a theoretical basis for clinical application.

亚甲基四氢叶酸脱氢酶2（methylenetetrahydrofolate dehydrogenase 2, MTHFD2）是一碳代谢途径的关键酶，参与调控肿瘤增殖和能量平衡。膀胱癌MTHFD2表达高于癌旁组织，但是MTHFD2是否影响膀胱癌恶性进展及其机制并不明确。我们发现，高表达MTHFD2促进膀胱癌细胞增殖，敲除MTHFD2抑制增殖。癌基因c-Myc参与调节细胞分裂和转化，其蛋白稳定性受PI3K/AKT通路调控。高表达MTHFD2激活AKT并上调c-Myc，敲除MTHFD2抑制AKT活化并降低c-Myc。我们拟在此基础上，以MTHFD2为靶点，通过高表达和敲除MTHFD2、恢复c-Myc，联合PI3K/AKT通路抑制剂或激动剂等，探讨MTHFD2是否通过PI3K/AKT/c-Myc通路调节代谢影响膀胱癌恶性增殖，揭示MTHFD2作为膀胱癌治疗靶点的潜在可能性，为临床治疗提供理论依据。

亚甲基四氢叶酸脱氢酶-2（methylenetetrahydrofolate dehydrogenase 2，MTHFD2）是一碳代谢途径的关键酶，参与调控肿瘤的增殖和能量平衡。生物信息学分析和前期研究中我们发现，膀胱癌中MTHFD2表达水平高于癌旁组织，并且与患者预后不良相关。但是MTHFD2影响膀胱癌恶性进展及其主要的作用机制目前并不明确。我们研究发现，高表达MTHFD2促进膀胱癌细胞恶性增殖和转移，敲减MTHFD2抑制细胞增殖和转移。体内研究也发现MTHFD2抑制剂LY345899和shRNA敲减MTHFD2表达均能显著抑制膀胱癌细胞的成瘤能力和增殖能力。通过RNA-seq技术筛查敲减MTHFD2对膀胱癌细胞基因表达谱变化，发现3711个基因表达水平改变，1997个基因表达下调，1714个基因表达上调。生信分析、RNA-seq及研究结果均证实膀胱癌中MTHFD2与癌基因C-MYC表达呈正相关，C-MYC富集基因与嘌呤和嘧啶代谢密切相关。说明MTHFD2可能通过C-MYC信号调节代谢影响膀胱癌恶性增殖，揭示MTHFD2作为膀胱癌治疗靶点的潜在可能性，为临床治疗提供理论依据。