B7-H3通过IDH1调控脂代谢影响结直肠癌增殖的机制研究

Colorectal cancer (CRC) is one of the most common malignant tumors. In addition to its immunosuppressive effect, immune checkpoint protein B7-H3 can also regulate the development of tumors through non-immunological mechanisms. The applicant has previously found that B7-H3 can regulate lipid metabolism reprogramming and promote CRC cell proliferation. Preliminary mechanism studies have found that B7-H3 can bind to isocitrate dehydrogenase (IDH1), the key enzyme of lipid metabolism, and down-regulation of IDH1 significantly inhibits the ability of cell proliferation by B7-H3. Moreover, B7-H3 and IDH1 are positively correlated in CRC tissues and are related to poor prognosis of patients. Based on these findings above, we hypothesized that B7-H3 might promote CRC cell proliferation by binding and up-regulating IDH1 expression. The project aims to systematically prove this hypothesis by using technical means such as cell, molecular biology and experimental zoology. The correlations between B7-H3, IDH1, clinicopathological parameters including serum lipid and prognosis are determined through clinical sample analysis. Therefore, this study will combine immune molecules and metabolic pathways to reveal the molecular mechanism of B7-H3 regulating the occurrence and development of CRC from a new perspective, and provide the important guidance for its clinical diagnosis and treatment.

结直肠癌（CRC）是常见的恶性肿瘤之一，免疫卡控点蛋白B7-H3除了发挥免疫抑制作用外，还可通过非免疫学机制调控肿瘤发生发展。申请人前期发现B7-H3能够调控脂代谢重编程，并促进CRC细胞增殖，初步机制研究发现B7-H3可与脂代谢关键酶异柠檬酸脱氢酶（IDH1）结合，下调IDH1显著抑制B7-H3的促细胞增殖能力；且两者在CRC组织中表达正相关并与患者预后不良有关。基于此，我们提出科学假说：B7-H3可能通过结合并上调IDH1表达促进CRC细胞增殖。本项目拟结合细胞、分子生物学和实验动物学等技术手段系统证明这一假说，并通过临床样本分析明确B7-H3、IDH1与血脂等临床病理参数及预后的相关性。因此，本课题将免疫分子和代谢途径相结合，从新的角度揭示B7-H3调控CRC发生发展的分子机制，为其临床诊断治疗提供重要指导。

结直肠癌（CRC）是最常见的恶性肿瘤之一，全球发病率和死亡率均位居第三。近年来，我国CRC发病率也呈逐年上升趋势，因此急需从发病机理入手，寻找有效地治疗方法改善CRC患者总体预后较差的现状。免疫卡控点蛋白B7-H3是I型跨膜糖蛋白，属于B7/CD28免疫球蛋白超家族，广泛表达于多种免疫细胞。除了发挥免疫抑制作用外，B7-H3还可通过非免疫学机制调控肿瘤发生发展，在多种恶性肿瘤中异常表达。项目负责人所在课题组发现，B7-H3在CRC中高表达，并与疾病进展和预后密切相关。因此，B7-H3被认为是新的肿瘤标志物和免疫治疗的潜在靶点。本项目通过细胞生物学和分子生物学等实验方法，检测B7-H3高表达或敲降表达的CRC稳转细胞株的细胞增殖能力和脂代谢变化，以及B7-H3与脂代谢关键酶异柠檬酸脱氢酶（IDH1）的调控关系，并在临床样本中验证两者表达关系，旨在探讨B7-H3对CRC脂代谢重编程及肿瘤进展中发挥的功能。研究结果初步表明，B7-H3可结合并上调IDH1的表达重编程CRC脂代谢从而促进细胞增殖，而具体分子机制仍需进一步探讨。本项目资助的衍生课题通过蛋白质组学预测、体外细胞实验、体内动物模型和临床样本验证等多途径，初步证实B7-H3可促进CRC细胞迁移侵袭，可结合并正性调控CYP1B1的表达促进CRC对5-Fu的耐药，也可调控FDX1的表达抑制铜死亡通路，还可结合糖代谢标志物等临床参数预测患者生存。以上结果均证实B7-H3在CRC的疾病进展过程中发挥重要作用，为深入探讨B7-H3参与调控的分子机制提供理论依据，并为临床以B7-H3为靶点进行诊断治疗提供重要指导。