脂肪酸氧化通路酶ECHS1失活致代谢重编程并诱发肾癌的分子机制

Abnormal accumulation of fatty acids is an important pathological feature of clear cell renal cell carcinoma (ccRCC), however the occurrence reason and pathogenic mechanism is not clear. Our previous study found that inactivation of ECHS1 lead to accumulation of fatty acids and branch-chain amino acid, and then promote cell proliferation and tumor development (Nat Commun, 2017). Our follow-up study found inactivation of ECHS1 up-regulated the transcription of FASN and promote de novo synthesis of fatty acids, and expression of ECHS1 in ccRCC was down-regulated remarkably and was associated with disease progression and poor prognosis, indicating ECHS1 reprogram fatty acid metabolism and play an important role in occurrence and progression of ccRCC. Moreover, we found inactivation of AMPK down-regulated transcription of ECHS1, and down-regulation of ECHS1 inhibited AMPK in a positive feedback way, which further down-regulated transcription of ECHS1. We conclude therefore that inactivation of AMPK in ccRCC inhibit transcription of ECHS1, and then reprogram fatty acid metabolism, which lead to accumulation of fatty acids and promote occurrence of ccRCC. In this project, we will explore 1) the molecular mechanism of inactivation of AMPK down-regulate transcription of ECHS1, 2) how inactivation of ECHS1 reprogram fatty acid metabolism, 3) how inactivation of AMPK-ECHS1 pathway promote occurrence of ccRCC in cell lines, Echs1+/- mouse and human ccRCC tissues, respectively. These results will provide a new idea in illuminating the mechanism of ECHS1 reprogram fatty acid metabolism and promote occurrence of ccRCC, and provide a new perspective for the diagnosis and prognosis evaluation for ccRCC.

脂肪酸异常累积是肾透明细胞癌的病理特征，其发生原因和致病机制不明。申请人前期发现，ECHS1失活可累积脂肪酸和支链氨基酸，促进细胞增殖和肿瘤发生（Nat Commun，2017）。后续发现ECHS1失活可激活FASN转录从而促进脂肪酸从头合成，而ECHS1在肾癌中显著下调并与疾病进展和不良预后相关，提示ECHS1重编程脂肪酸代谢并参与肾癌发生发展。还发现AMPK失活下调ECHS1，下调的ECHS1正反馈抑制AMPK活性，进一步下调ECHS1的转录。据此推测，肾癌中AMPK失活抑制ECHS1转录，进而重编程脂肪酸代谢，累积脂肪酸并诱发肿瘤。本项目拟在细胞、动物和临床样本层面探明1）AMPK失活下调ECHS1转录的分子机理；2）ECHS1失活如何重编程脂肪酸代谢；3）AMPK-ECHS1轴失活如何诱发肾癌。预期成果将揭示ECHS1重编程脂肪酸代谢并诱发肾癌的新机制，为肾癌诊断和预后提供新视角。

透明肾细胞癌（clear cell renal cell carcinoma, ccRCC）是肾癌最常见的病理类型。脂肪酸异常累积是肾透明细胞癌的病理特征，其发生原因和致病机制不明。申请人前期研究发现，ECHS1失活可累积脂肪酸和支链氨基酸，促进细胞增殖和肿瘤发生（Nat Commun，2017）。在本项目的支持下课题进展顺利，我们探讨脂肪酸代谢酶ECHS1在肾透明细胞癌组织中下调的生物学效应并首次探究ECHS1下调的具体分子生物学机制。通过细胞培养、RNA干扰、免疫印迹、免疫组织化学、油红染色、GC-MS、基因敲除、凝胶迁移实验、双荧光素酶报告基因检测和染色质免疫共沉淀等多种分子生物学技术，分别从细胞水平、动物水平和肾透明细胞癌患者的临床标本这三个层面来探讨代谢酶ECHS1在肾透明细胞癌发生中的作用及分子调控机制。结果显示，转录因子GATA3正向调控ECHS1启动区的转录活性，肾透明细胞癌组织中AMPK的失活会下调GATA3的水平，进而从转录水平下调ECHS1的表达，ECHS失活通过激活mTOR信号通路及脂肪酸从头合成促进细胞增殖，从而促进肾透明细胞癌的发生。此外，我们还发现mTOR信号通路的激活可以进一步抑制AMPK的活性，从而形成对ECHS1转录的正反馈抑制。本研究成果揭示ECHS1失活重编程脂肪酸代谢并诱发肾透明细胞的分子生物学机制（AMPK-GATA3-ECHS1信号轴），不仅从代谢的角度为阐明肾透明细胞癌的发生机制提供新的思路，也为肾透明细胞癌的临床治疗提供新的药物靶点，为精准医疗提供实验依据。该研究成果“Inactivation of the AMPK-GATA3-ECHS1 Pathway induces Fatty Acid Synthesis that Promotes Clear Cell Renal Cell Carcinoma Growth”于2020.1发表于国际权威期刊《Cancer Research》（IF：12.701，申请人为第一作者）。

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