FOXM1和CIP2A双向正反馈调节在肝细胞癌发生进展中的作用和机制研究

Hepatocellular carcinoma (HCC) seriously endangers the health of Chinese people. To elucidate the key molecular network in the development of HCC is very important to establish effective treatment methods. The transcription factor Forkhead box protein M1(FoxM1)is a key transcription factor in cell mitosis. In recent years, a large number of studies have shown that the abnormal high expression of FoxM1 plays a role in tumor progression by accelerating cell proliferation. The activity of FoxM1 is affected by the dynamic regulation of serine phosphorylation. Studies have shown that the regulatory subunit B55α of protein phosphatase 2A(PP2A)is closely associated with FoxM1 , and inhibits its activity by dephosphorylating the serine site of FoxM1. The applicant's previous results showed that FoxM1 was positively correlated with the expression of CIP2a, Which was an inhibitor of PP2A phosphatase, in hepatocellular carcinoma. At the same time, FoxM1 may have transcriptional activation effect on CIP2a. Therefore, we speculate that FoxM1 and CIP2a may have a bidirectional positive feedback regulation relationship in hepatocellular carcinoma. In this project, we intend to elucidate the mechanism of positive feedback regulation and its biological significance in the occurrence and development of hepatocellular carcinoma from the molecular, cellular, animal models and clinical samples. This will provide an important basis for revealing the signal network in the occurrence and development of hepatocellular carcinoma and exploring new therapeutic targets.

肝癌严重危害国人健康，深入阐明该疾病发生发展的关键分子网络，对建立有效的治疗手段至关重要。FoxM1是细胞有丝分裂中发挥关键作用的转录因子，近年来的大量研究显示FoxM1的异常高表达通过加快细胞增殖在肿瘤进展中发挥功能。FoxM1自身的活性受到丝苏氨酸磷酸化动态的影响。有研究证明：抑癌磷酸酶PP2A的调节亚基B55α与FoxM1发生互做，并通过对FoxM1丝苏氨酸位点的去磷酸化抑制其活性。申请人的前期研究结果显示：FoxM1与PP2A磷酸酶的抑制因子CIP2a在肝癌组织中的表达呈现显著正相关。同时，FoxM1对CIP2a可能存在转录激活作用。据此，我们推测FoxM1和CIP2a在肝癌中可能存在双向正反馈调节关系。在本项目中，我们拟从分子、细胞、动物模型和临床样品等层面阐明两者间正反馈调节的机制和在肝癌发生发展中的生物学意义，这将为揭示肝癌发生发展中的信号网络并挖掘新的治疗靶标提供重要依据。

肝癌严重危害国人健康，深入阐明该疾病发生发展的关键分子网络，对建立有效的治疗手段至关重要。FoxM1是细胞有丝分裂中发挥关键作用的转录因子，近年来的大量研究显示FoxM1的异常高表达通过加快细胞增殖在肿瘤进展中发挥功能。FoxM1自身的活性受到丝苏氨酸磷酸化动态的影响。有研究证明：抑癌磷酸酶PP2A的调节亚基B55α与FoxM1发生互做，并通过对FoxM1丝苏氨酸位点的去磷酸化抑制其活性。申请人的前期研究结果显示：FoxM1与PP2A磷酸酶的抑制因子CIP2a在肝癌组织中的表达呈现显著正相关。同时，FoxM1对CIP2a可能存在转录激活作用。据此，我们推测FoxM1和CIP2a在肝癌中可能存在双向正反馈调节关系。. 在本项目中，我们从分子、细胞、动物模型和临床样品等层面阐明两者间正反馈调节的机制和在肝癌发生发展中的生物学意义。上述发现对理解FoxM1的磷酸化动态调控具有理论意义，而联合FoxM1、NEK2和CIP2A作为预后指标能够为肝癌患者预后提供更为准确的生物标志；由于FoxM1在肿瘤中具有重要的促癌作用，但由于其为转录因子在结构上存在不确定性，难以成药，因此靶向FoxM1磷酸化动态调控的过程进行药物研发能够为FoxM1高表达的肝癌患者的治疗提供有意义的策略。