DDX39B通过调控PKM2介导能量代谢促进结直肠癌生长转移的机制研究

结直肠癌是常见的恶性肿瘤之一，能量代谢异常在结直肠癌发生发展中发挥重要作用，但其分子机制仍有待进一步阐明。我们前期研究发现DDX39B在结直肠癌组织中表达显著高于癌旁正常组织，并且在结直肠癌肝转移灶组织中的表达相对于原发灶组织显著上调，过表达DDX39B能够促进结直肠癌细胞生长和转移；我们还发现DDX39B与PKM2直接结合并增强PKM2蛋白的稳定性，促进PKM2核内转运，增强结直肠癌细胞对葡萄糖的摄取、乳酸和ATP的产生以及PKM2下游靶基因的转录。本项目拟在前期工作基础上，利用多种细胞和动物模型，明确DDX39B在结直肠癌细胞生长转移和能量代谢中的作用，阐明DDX39B通过促进PKM2蛋白稳定性、核内转运等方式调控PKM2功能改变细胞能量代谢进而促进结直肠癌细胞生长转移的分子机制，并结合临床样本明确DDX39B/PKM2信号轴作为结直肠癌预后标志物和治疗靶标的潜在临床应用价值。

Colorectal cancer (CRC) is one of the most common malignancies causing global public health burden. Altered energy metabolism, one of the hallmarks of tumor cells, plays a critical role in the progression and metastasis of CRC, but the mechanismsare not fully understood. In our previous study, we found increased expression of DDX39B in CRC tissues compared with adjacent noncancerous mucosa. Moreover, stronger DDX39B staining was observed in CRC liver metastasis tissues compared with primary CRC tissues. Up-regulated DDX39B significantly promoted the growth and metastasis of CRC cells. We demonstrated that DDX39B directly interacted with PKM2, resulting in increased the stability and nuclear translocation of PKM2 protein, subsequently augmenting the transcription of PKM2 target genes and leading to increased glucose uptake, lactate and ATP productions in CRC cells. In the present project, we aim to further uncover the role in the growth, metastasis and energy metabolism of CRC, and investigate the molecular mechanism underlying DDX39B-regulated PKM2 functions in the growth and metastasis of CRC. We also will evaluate the pathological correlations of DDX39B/PKM2 axis with progression and prognosis of CRC patients. Our study will highlights the significance of DDX39B/PKM2 axis in the progression and metastasis of CRC, and clarify DDX39B/PKM2 axis as a predictor of prognosis in CRC patients and a potential therapeutic target for CRC.