转录因子FOXM1通过调控KIF4A和TPX2基因表达促进肝癌细胞增殖和肿瘤生长的分子机制

The transcription factor FOXM1 is an important molecule that controls the growth of cells, and its abnormal expression is closely related to the occurrence of multiple tumors including hepatocellular carcinoma. But the pathophysiological mechanism remains unclear. Through data mining, we found that cell mitotic gene, FOXM1, TPX2 and KIF4A, were highly expressed in liver cancer tissues and correlated with poor survival prognosis of patients. Bioinformatics prediction: KIF4A and TPX2 genes may be regulated by FOXM1 at the transcription level; The relevant experimental evidence obtained suggests that KIF4A is the direct target gene of FOXM1. High expression of FOXM1 and KIF4A can promote the proliferation of hepatocellular carcinoma cells. The expression of TPX2, KIF4A and FOXM1 in human liver cancer tissues was significantly higher than that of adjacent tissues. Therefore, we hypothesized that FOXM1 promotes the proliferation of hepatocellular carcinoma cells and tumor growth by regulating the expression of KIF4A and TPX2 genes. This topic will explore the role of the FOXM1-KIF4A signal axis and FOXM1-TPX2 signal axis in the proliferation and tumor growth of hepatocellular carcinoma cells at the molecular level, cell level, animal level and clinical cohort. And the biological function of the signal network will be clarified. The research results will provide a new basis for the pathogenesis of hepatocellular carcinoma and provide a new target for the diagnosis and treatment of hepatocellular carcinoma.

转录因子FOXM1是控制细胞生长的重要分子，其异常表达与包括肝癌在内的多种肿瘤的发生密切相关，但病理生理机制仍有待明晰。通过数据挖掘，我们发现细胞有丝分裂相关基因FOXM1、KIF4A、TPX2在肝癌组织中高表达并与患者的不良预后相关；生物信息学预测KIF4A和TPX2可能被FOXM1转录调控；已获取的实验证据提示KIF4A是FOXM1的直接靶基因；高表达FOXM1和KIF4A能促进肝癌细胞增殖；人肝癌组织中FOXM1、KIF4A和TPX2的表达明显高于癌旁组织。据此我们假设FOXM1通过调控KIF4A和TPX2基因的表达促进肝癌细胞增殖及肿瘤生长。本课题将采用多学科手段在分子、细胞、动物和临床队列等多个层面探讨FOXM1-KIF4A信号轴和FOXM1-TPX2信号轴在肝癌细胞增殖和肿瘤生长中的作用，阐明该信号网络的生物学功能。研究成果将为肝癌的发病机理提供新依据，为肝癌的诊疗提供新靶点。

原发性肝细胞癌是我国常见的恶性肿瘤，虽然已有多篇文章报道：转录因子FOXM1在细胞增殖调控过程中发挥重要作用，其异常表达与肿瘤的发生密切相关；有丝分裂相关驱动蛋白KIF4A和微管募集蛋白TBX2与细胞增殖的关系密切。然而，FOXM1是如何调控细胞有丝分裂，进而促进肿瘤细胞增殖的分子机制尚不清晰。本项目以转录因子FOXM1为中心，从分子水平、细胞水平、动物模型以及临床队列四个层面，研究“FOXM1-KIF4A信号轴”和“FOXM1-TBX2信号轴”对肝癌细胞增殖和肿瘤生长的作用及具体机制，研究取得以下结果：第一，分析了肝癌组织和癌旁组织中FOXM1和KIF4A及TPX2的基因及蛋白表达水平以及KIF4A和TPX2表达水平与FOXM1表达水平的相关性，明确了FOXM1和KIF4A和TPX2表达水平变化的因果关系及生物学意义；第二，发现有丝分裂相关驱动蛋白KIF4A和微管募集蛋白TBX2作为靶基因在转录水平受转录因子FOXM1的直接调控；第三，发现Hedgehog信号通路的异常活化通化过转录因子Gli2调控FOXM1表达以及异常调控的Hh/Gli2-FOXM1-TPX2信号轴在肝癌细胞增殖中的关键作用；第四，通过生物信息学、细胞生物学、分子生物学、实验动物学等多学科手段，阐明了“异常表达的转录因子FOXM1通过调控KIF4A和TBX2基因表达促进肝癌细胞增殖和肿瘤生长”。总之，我们的研究阐明了一个新的调控机制，即：转录因子FOXM1-有丝分裂相关驱动蛋白KIF4A/微管募集蛋白TBX2调控网络促进肝癌细胞增殖及肿瘤生长。我们的发现为肝癌的发病机理提供了新的理论依据，并为其诊断及治疗提供了新的潜在靶点。