MET-MCD负反馈调节环路在肾癌转移中的作用及分子机制研究

肥胖是包括肾癌在内的多种肿瘤的重要风险因素，而转移是肾癌致死的主要诱因。因此，阐明肥胖所伴随的脂代谢紊乱与转移之间的关系有着重要的临床指导意义。MCD是负责调控脂肪酸合成的重要代谢酶，其肿瘤学功能存在很大争议。申请人预实验发现MCD与患者生存率正相关，肾癌驱动基因MET抑制MCD的表达，反之，MCD又反馈抑制MET活化。据此，申请人提出科学假说：肾癌中存在MET-MCD负反馈调控环路；MCD通过抑制脂肪酸合成影响膜脂组分，阻断跨膜受体酪氨酸激酶MET活化，从而抑制肾癌转移；在肾癌早期，MCD介导脂肪酸氧化从而促进肾癌细胞增殖，加速肿瘤生长；随着肾癌进展到晚期，MET在特定条件下触发，通过活化STAT3或失活AMPK，抑制MCD表达或活性，从而促进脂肪酸合成并介导肾癌转移。该研究提出一条全新的代谢网络与肿瘤信号互作的通路，同时提示MCD可以作为转移性肾癌的潜在标志物和治疗靶标。

Metastasis is among one of the major contributing factor of renal cell carcinoma (RCC)-associated mortality. Recently, escalating epidemiology studies reveal that obese, a complex disorder involving deregulated lipid metabolism, is a master risk factor in multiple cancers including RCC. Therefore, a better understanding of the relationship between lipid metabolism and metastasis may contribute to the development of precision medicines targeting to metabolic network for metastatic cancer. Malonyl-CoA decarboxylase (MCD) catalyzes the conversion of malonyl-CoA to acetyl-CoA, thus prevents lipogenesis and meanwhile facilitates fatty acids oxidation (FAO). So far, the function of MCD in cancer is highly debatable. Our pilot study demonstrates that oncogenic MET inhibits MCD expression. By contrast, overexpression of MCD, instead of enzymatic dead mutant, compromises MET phosphorylation. As a result, we here identify a novel MET-MCD negative feedback regulatory loop in metastatic RCC, and propose our hypothesis as below: In early stage of RCC, MCD function as an oncogene to promote cell proliferation via the induction of FAO. As the malignant grade progresses, a certain type of signal triggers MET activation, resulting in STAT3 phosphorylation or AMPK dephosphorylation, which represses MCD and eventually leads to metastasis. Furthermore, we propose that MCD is able to reprogram the composition of membrane lipid and block the phosphorylation of membrane receptor tyrosine kinase MET, thus srppress RCC metastatic transformation. Through this proposed project, we will further validate the tumor suppressive function of MCD specifically in term of RCC metastasis, delineates molecular mechanisms underlying MCD repression by MET, as well as MET inhibition by MCD. Even importantly, we will pinpoint the molecular trigger through which MET-MCD feedback loop is activated specifically in metastatic RCC. Overall, findings from this proposal reveal a novel pathway through which cancerous signaling cross-talks with metabolic networks, as expands our knowledge of cancer metabolism and shed light on the development of tumor biomarker as well as anti-cancer therapeutic strategies, at least in term of RCC.