RNA结合蛋白Nucleolin通过调控PKM2促进结直肠癌发生发展的机制研究

Colorectal cancer (CRC) is a serious threat to human health and the 3rd leading cause of cancer-related incidences and mortalities. Though there is available data on CRC，the detailed mechanisms of CRC remains unclear. Previous data suggested that RNA binding protein Nucleolin plays oncogenic roles in CRC, but numerous details are missing in this link. By conducting systematic experiments, we discovered a Nucleolin interactor, hnRNPA1, that directly binds to Nucleolin under PKM2 mRNA conditions. The PKM2 alternative splicing occurred in the nucleus and was regulated by hnRNPA1. Based on these new findings, we hypothesis that Nucleolin enhances hnRNPA1-mediated PKM2 alternative splicing and then transports PKM2 mRNA from nucleus into cytoplasm by binding with hnRNPA1, resulting the increases of PKM2 protein expression in cytoplasm that promotes glucose metabolism and tumor development. The present study will try to reveal a novel pathway of Nucleolin-hnRNPA-PKM2 and its effects on glucose metabolism and tumor development in CRC by using the molecular assays as well as clinical samples analysis. This study reveals the new mechanism of Nucleolin regulated hnRNPA1-PKM2 pathway in the glucose metabolism that may serve as a prognostic biomarker and/or an effective target for CRC therapies.

结直肠癌是严重威胁人类健康的恶性肿瘤，其发病率和死亡率均位列全球第三位，至今其发病机制尚未充分了解。RNA结合蛋白核仁素(Nucleolin)在结直肠癌中发挥着癌基因的作用，但具体的分子机制尚不清楚。我们前期发现Nucleolin可与核不均一核糖核蛋白A1(hnRNPA1)结合，PKM2 mRNA是影响其结合的关键因素，并且hnRNPA1可促进细胞核中PKM2的可变剪切。据此我们假设，Nucleolin可能通过与hnRNPA1结合，影响其对PKM2 mRNA的可变剪切，并能进一步携带PKM2 mRNA由胞核向胞浆转位，从而增加胞浆中PKM2蛋白水平，进而调控肿瘤细胞糖代谢，促进肿瘤的发生发展。本研究拟通过分子实验及临床标本验证揭示Nucleolin通过hnRNPA1-PKM2通路调控结直肠癌糖代谢的新机制，为结直肠癌的防治提供新的思路。

结直肠癌是严重威胁人类健康的恶性肿瘤，其发病率和死亡率均位列世界第三。.结直肠癌的发病原因复杂，受遗传学、表观遗传学以及环境等共同调控。寻找导致癌症发生及发展的关键因素，筛选新的靶点有助于为癌症的诊断和治疗提供新思路。核仁素已被证实具有多重生物学功能并且在肿瘤患者中呈现特异性表达可被视为肿瘤诊断中的潜在生物标志物和治疗靶点。我们的研究结果发现在结直肠癌中核仁素的高表达与患者的预后不良有关。在对其机制进行进一步探讨时证实核仁素可以通过RNA介导与hnRNPA1蛋白-蛋白之间的相互作用。同时我们还阐明了核仁素在结直肠癌细胞葡萄糖代谢过程中发挥的功能及详细的作用机制。核仁素主要通过促进hnRNPA1对PKM的可变剪接进而促进结直肠癌细胞的糖酵解代谢途径。以核仁素为靶标，进行纳米探针-AS1411靶向药物设计有助于延缓结直肠癌的发生及发展。通过上述的研究证实了核仁素在结直肠癌进展中的功能及作用机制，核仁素可能是结直肠癌重要的诊断指标及潜在的治疗靶点。