脂肪酸代谢重编程在甲状腺乳头状癌中的作用及机制研究

Papillary thyroid carcinoma (PTC) is a kind of malignant tumor with high incidence and large population. The pathogenesis of PTC has not been completely elucidated so far. Metabolic reprogramming is a common feature of tumors. The study of PTC reprogramming is not only helpful to elucidate the pathogenesis of PTC in terms of metabolism, but also provides a new target for prevention and early diagnosis and treatment. At present, there are few studies on PTC related metabolic reprogramming, which is mainly confined to the description of the metabolic components of PTC, and the key metabolites and their regulatory pathways that influence the development of PTC are not clear. Our previous studies found that the level of fatty acids in PTC decreased obviously, and associated with clinical stage, suggesting that the metabolic reprogramming of fatty acids may be involved in the occurrence and development of PTC. Therefore, we hypothesize that the metabolic reprogramming of fatty acids plays an important role in the occurrence, invasion and metastasis of PTC. To test this hypothesis, this project intends to use the omics technology to reveal the metabolic profiling in PTC, screening the key differential fatty acids and its regulatiory pathway in PTC and to explore the molecular mechanism involved in growth, invasion and metastasis of the key differential fatty acids and its regulatiory pathway. The applicant has long been engaged in the study of metabonomics in thyroid cancer. With obvious innovation in combining with the omics technology and subsequent research of mechanism, this project has important theoretical significance and potential practical value.

甲状腺乳头状癌（PTC）是一种发病率高、病人群体庞大的恶性肿瘤，其发病机制尚未阐明。代谢重编程是肿瘤的共同特征，逆转代谢重编程可特异性消除肿瘤。不同肿瘤呈现不同的代谢重编程，目前PTC相关的代谢重编程研究尚少，且主要局限于表象性描述代谢成分改变，影响PTC发生发展的关键代谢物及其调控通路尚不清楚。申请者前期研究发现，PTC脂肪酸代谢明显异常，且与临床分期相关，提示脂肪酸代谢重编程可能参与PTC的发生发展。据此，申请者提出假说，脂肪酸代谢重编程在PTC发生、侵袭及转移中发挥重要作用。为验证这一假说，本课题拟利用组学技术揭示PTC脂肪酸代谢谱，筛选与PTC发生发展相关的关键差异脂肪酸及其调控通路，探讨差异脂肪酸及其调控通路参与PTC生长、侵袭及转移的分子机制。申请者长期从事甲状腺癌组学相关研究，工作基础良好。课题结合组学技术与机制研究，创新性明显，具有重要理论意义与潜在应用价值。

本课题遵照既定研究计划进行，结合最新进展，执行过程中对计划进行了部分调整和补充，加入了探索实验，达到课题预期目标并有新突破。经费使用合理有效，有多篇标注本课题的论文发表。.甲状腺乳头状癌(PTC)是一种发病率高、病人群体庞大的恶性肿瘤，其发病机制尚未阐明。代谢重编程是肿瘤的共同特征，逆转代谢重编程可特异性消除肿瘤。不同肿瘤呈现不同的代谢重编程，目前PTC相关的代谢重编程研究尚少，并且主要局限于表象性描述代谢成分改变，影响PTC发生发展的关键代谢物及其调控通路尚不清楚。申请者前期研究发现，PTC脂肪酸代谢明显异常，且与临床分期相关，提示脂肪酸代谢重编程可能参与PTC的发生发展。据此，申请者提出，脂肪酸代谢重编程在PTC发生、侵袭及转移中发挥重要作用。.为此，课题组利用脂质组学、蛋白组学和代谢组学分析全面揭示了PTC脂质代谢谱，明确了与PTC发生发展密切相关的关键差异脂质、差异蛋白及差异代谢物，为PTC早期诊断和机制研究提供了新的实验数据；脂质组学和蛋白组学的结果表明长链脂肪酸储备减少，脂类转运和脂肪酸氧化活跃；利用多组学整合分析首次系统揭示了PTC脂肪酸代谢通路的水解、转运和氧化环节均活化明显，经实验验证明确了脂肪酸代谢关键酶(LPL,FATPs,CPT1)参与PTC侵袭及转移的分子机制，为从代谢角度阐明PTC的发生机制提供了新的实验依据，为防治PTC提供有价值的新靶点；探索实验首次发现新型抑癌基因ZHX2在PTC中表达显著下调，经一系列实验验证了ZHX2通过调控下游蛋白S100A14抑制PTC的发生发展。.综上，本课题按时完成既定研究计划并有新突破，经费使用合理，结合多组学技术、整合分析与机制研究，创新性明显，研究成果丰富，为从代谢角度阐明PTC的发病机制，以及进行PTC的临床早期精确诊断和靶向治疗提供了新思路，具有重要理论意义与潜在应用价值。