基于MAPK10调控的ROS代谢途径在肝癌发生发展中的作用机制研究

Hepatocellular carcinoma (HCC) is one of the most common fatal malignances of the digestive system and ranks the second leading cause of cancer death in China. Increased generation of reactive oxygen species (ROS) and an altered redox status has been implicated in hepatocarcinogenesis. Yet, the molecular mechanisms underlying ROS modulation in HCC remain largely unclear. Earlier studies from our.group found that MAPK10 was frequently downregulated in liver cancer cells. Moreover, we have preliminary evidence that ectopic expression of MAPK10 has strong tumor suppressive ability in HepG2 cells. Furthermore, we provide another interesting evidence that MAPK10 could dramatically reduce mitochondrial ROS levels in HepG2 cells. Taken together, we propose to investigate the role of MAPK10 as a novel tumor suppressor gene associated with ROS metabolism in HCC. The objectives in the present proposal will be achieved through the following interrelated specific aims: to characterize the tumor suppressive role of MAPK10 in HCC; to investigate the mechanisms underlying the antioxidant role of MAPK10 in HCC; and to study the clinical significance of the inactivation of MAPK10 in HCC. These research objectives will be tackled with a multidisciplinary approach combining biochemistry, molecular and cell biology, metabolomics and animal model. The new knowledge gained from this proposed study will provide considerable insight into the role of MAPK10 in redox modulation during HCC progression, advance our understanding of liver cancer metabolism, and facilitate more effective strategy for HCC treatment.

肝细胞癌（HCC）是恶性程度极高的消化道肿瘤之一，是我国肿瘤的第二大死因。活性氧（ROS）的产生过剩和氧化还原平衡状态的改变都与肝细胞癌的发生相关，但分子机制仍不明确。我们前期研究发现MAP激酶家族成员MAPK10（或JNK3）在肝癌细胞系及临床组织样本普遍下调。此外，MAPK10还能够抑制肝癌细胞的增殖和迁移能力、减少线粒体ROS的产生以及抑制DNA氧化损伤。据此我们推测：MAPK10是一个通过调控肝癌细胞ROS代谢途径以降低肝癌恶性演进过程的新型抑癌基因。本研究拟通过体内外功能实验、线粒体代谢组学和临床样本验证等方法，深入研究1）MAPK10在肝癌细胞中的肿瘤抑制效应；2）MAPK10在肝癌细胞中的抗氧化作用机制；以及3）肝癌细胞中MAPK10失活的临床意义，进一步揭示肝癌的发病新机制，为肝癌个体化精准诊疗的完善和新型抗癌方案的设计提供强有力的理论依据。

肝细胞癌（HCC）是恶性程度极高的消化道肿瘤之一，也是我国肿瘤患者的第二大死因。肝癌的不良预后与肿瘤微环境中的活性氧（ROS）产生过剩所导致的氧化还原平衡状态改变以及肝癌细胞的免疫逃逸密切相关。我们前期研究发现：MAP激酶家族成员中的MAPK10/JNK3在肝癌细胞系及临床组织样本普遍下调。此外，MAPK10激酶的表达可受到具有抗氧化功能的抑癌基因SLC22A3的正调控,提示肝细胞癌变过程中MAPK10的表达下调可能是促进肝癌发生发展的危险因素。在本项目中，我们发现MAPK10基因的表达下调与肝癌患者的不良预后呈正相关。体外细胞实验显示MAPK10在肝癌细胞中具有显著的抑癌功能以及抗氧化作用。生信分析结果显示在肝癌患者中MAPK10失活可下调肝癌肿瘤微环境的免疫活性。进一步的分子机制研究发现，在HCC细胞中活化的MAPK10激酶可通过促进转录因子c-jun蛋白丝氨酸位点（Ser63）的磷酸化从而上调免疫共刺激因子ICAM1的表达，最终增强肝癌患者肿瘤微环境的免疫活性以及促进免疫细胞浸润。综上所述，本项目不仅揭示了肝癌细胞中MAPK10介导的抗氧化作用缺失促进肝癌发生发展的新机制，而且还发现了肝细胞癌变过程中MAPK10表达下调或失活可导致肝癌免疫抑制性微环境的形成, 最终促进肝癌细胞发生免疫逃逸或肿瘤远处转移。上调MAPK10激酶在肝癌细胞中的表达及活性可能提高未来肝癌患者临床治疗效果。