脂肪酸转运蛋白5介导的脂质代谢重编程在肝癌恶性进展中的作用和机制研究

The rapid, uncontrolled proliferation of malignant cells requires a constant supply of energy and macromolecular building blocks. To meet these demands, cancer cells must reprogram their metabolic pathways and show abnormal metabolic alterations. With going deep into studying, reprogramming of energy metabolism has been recognized as an emerging hallmark of cancer. It is well known that one of the most prominent defining metabolic alterations in hepatocellular carcinoma (HCC) is dysregulated fatty acid (FA) metabolism. Previous study demonstrated that enhanced FA synthesis was involved in HCC development and progression. In addition, another main source of FAs in cancer cells is the direct uptake and transport of free FAs from the external environment. Although most tumors exhibit a metabolic shift toward de novo lipogenesis, the functional role and underlying mechanism of FAs transport pathway in HCC progression is still unclear. Our previous study revealed the molecular mechanisms by which the enhanced de novo FA synthesis could promote HCC cells survival and proliferation. On the basis of these findings, we identified fatty acid transport protein 5 (FATP5) as the critical enzyme in regulating exogenous FAs uptake and transport in HCCs. Meanwhile, we also observed that FATP5 was commonly low-expressed in HCC tissues compared with that in their matched nontumorous liver sections. Down-regulation of FATP5 in HCC samples was significantly associated with multiple malignant clinicopathological features of HCC. Consistently, patients with lower FATP5 expression exhibited much worse overall survival (OS) and recurrence-free survival rate (RFS), further indicating the requirement of FATP5 in HCC progression. More importantly, silencing of FATP5 enhanced membrane fluidity, glycolytic flux and ATP generation, thus causing the activation of mTOR signaling pathway to regulate the biological phenotypes of HCC cells. Therefore, we hypothesize that FATP5 may promote HCC progression through modulating metabolic reprogramming-related signal pathways. In this study, we will further explore the functional role of FATP5-mediated metabolic alterations in HCC tumorigenesis, and explain the underlying mechanism involved in dysregulated FAs metabolism by experiments both in vitro and in vivo. Moreover, we'll also clarify the significance of FATP5-mTOR signaling axis in predicting clinicopathological features and prognosis of patients with HCC. Our understanding of FATP5-mediated metabolic alterations and associated signaling pathways may contribute to the development of novel and efficient anti-tumor approaches for patients with HCC.

能量代谢重编程是恶性肿瘤的重要生物学特征之一。其中，脂代谢异常、尤其脂质从头合成途径的增强在肝癌进展过程中发挥重要作用。然而，脂质摄取和转运途径的异常是否调控肝癌的恶性生物学特性及其分子机制仍有待研究。前期结果显示，脂质摄取和转运途径的关键分子脂肪酸转运蛋白（FATP5）在肝癌中的表达显著低于癌旁组织，并与患者临床指标和预后密切相关；此外，FATP5的低表达可增强细胞膜流动性、糖酵解通路流量以及ATP的生成，进而激活mTOR信号通路来促进肝癌细胞增殖、存活和转移等。由此，我们推测FATP5可能通过介导代谢重编程来调控相关信号通路，进而影响肝癌的恶性进展。本项目拟深入研究FATP5对代谢模式的改变及其对肝癌细胞生物学特性的影响，探讨FATP5-mTOR通路的调控机制和在肝癌患者诊疗中的意义，旨在从脂代谢角度为肝癌的防治提供新的靶点和思路。

代谢模式的重编程是恶性肿瘤最重要的生物学特征之一，并在原发性肝癌（HCC）的发生发展中起到重要作用。脂肪酸转运蛋白（FATP5）主要参与外源性脂质摄取和跨膜转运的过程，但在HCC进展及转移中的具体作用和机制仍不清楚。在本项目中，课题组通过体外细胞分子实验、体内动物实验、临床患者样本以及网络肝癌数据库等多个层面系统的分析了FATP5在HCC中的作用。结果显示，FATP5在肝癌中明显处于低表达的状态，并且与肝癌患者恶性临床病理特征密切相关，而且FATP5低表达是肝癌患者术后易复发、预后不良的重要危险因素和预测因子。此外，FATP5的表达水平可显著影响肝癌细胞的迁移和侵袭能力，并且可以介导以糖酵解为主的代谢重编程并且改变胞内能量稳态。这种情况下会导致AMPK信号通路的激活，通过mTOR/S6K通路直接调控肝癌细胞EMT过程，参与细胞的迁移和侵袭。而干预AMPK/mTOR信号通路轴可明显改变肝癌细胞的迁移和侵袭能力，影响肝癌的进展和转移。基于以上结果，干预AMPK/mTOR通路可能是针对FATP5低表达的肝癌患者的有效治疗策略，进而从代谢的角度为肝癌治疗提供了新的靶点，具有较好的临床转化意义和应用前景。