C/EBPalpha-ACSL通路促进肝癌细胞存活和转移的基础和转化研究

Lipid metabolic reprogramming is important for liver cancer cell survival and metastasis. We recently reported that transcription factor C/EBPalpha was over-expressed in human primary Hepatocellular Carcinoma (HCC) and protected cancer cells from glucose starvation induced cell death through autophagy and lipid catabolism (Hepatology 2015). Our preliminary studies further found that C/EBPalpha up-regulated a group of Acyl-CoA Synthetases (ACSLs) that were involved in long-chain fatty acid metabolism, and inhibition of ACSL activity could sensitize HCC cells to starvation-induced cell death. We thus hypothesized that the putative C/EBPalpha-ACSL pathway may promote cancer cell survival and metastasis. We plan to study: 1) the clinical significance of ACSLs in HCC patient survival and recurrence; 2) the ability of ACSLs to promote cancer cell survival, migration and invasion, upon situations of nutrient repletion or metabolic starvation; 3) the ability of ACSLs to promote HCC growth and metastasis in a nude mice orthotopic xenograft model; 4) the molecular mechanisms of how C/EBPalpha up-regulated ACSLs. The results to be obtained will help clarify the oncogenic effects and clinical significance of the putative C/EBPalpha-ACSL pathway, and deepen our understandings in cancer lipid metabolic reprogramming.

脂肪代谢重编程对肝癌细胞存活和转移具有重要意义。我们最近报道了转录因子C/EBPalpha在人肝癌中高表达，并通过自噬和脂肪分解代谢保护细胞免于葡萄糖缺乏引起的细胞死亡(Hepatology 2015)。预实验发现C/EBPalpha调控一组活化长链脂肪酸的酰基辅酶A合成酶（ACSL），而抑制ACSL活性可促进葡萄糖缺乏引起的细胞死亡。因而提出以下研究假设：C/EBPalpha-ACSL通路可能促进肝癌细胞存活和转移。计划研究：1）ACSL对肝癌患者预后和复发的临床学意义；2）通过诱导沉默ACSL表达，研究其在营养充足或代谢性应激下促进存活、迁移和浸润的作用；3）通过裸鼠肝癌原位移植瘤模型，确定ACSL促进肝癌生长和肝内转移作用；4）最后研究C/EBPalpha调控ACSL表达的分子机制。预期结果将阐明C/EBPalpha-ACSL通路的促肝癌作用和靶向价值，深化肝癌脂肪代谢重编程的认识。

脂肪代谢重编程对于肝癌发生和发展具有重要意义。本课题组在2015年报道了肝癌组织高表达C/EBPalpha并通过其介导的脂肪自噬和脂肪分解代谢保护了细胞免于代谢性应激导致的细胞死亡（Hepatology. 2015 Mar;61(3):965-78）。在此基础上，本项课题研究了C/EBPalpha的下游基因ACSL4介导的脂肪酸代谢对肝癌细胞死亡影响的分子机制和临床意义。首先，我们发现ACSL4在肝癌组织中高表达，并与手术切除肝癌患者的不良预后相关。其次，ACSL4是索拉非尼（晚期肝癌的一线药物）导致肝癌细胞发生铁死亡的关键基因。敲除ACSL4或给予特异抑制剂可以阻断ACSL4介导的多不饱和脂肪酸代谢和脂质过氧化，最终阻断了铁死亡。更重要的是，肝癌组织中ACSL4的表达可以预示手术后索拉非尼辅助治疗的疗效。这个发现对于通过ACSL4作为预测标志物来选择肝癌病人进行索拉非尼精准治疗具有重要意义。再次，多种小分子药物（如青蒿琥酯和槲皮素）可以通过载铁蛋白自噬促进载铁蛋白降解和游离铁的释放，从而促进索拉非尼导致的铁死亡。青蒿琥酯可以和低剂量的索拉非尼联合诱导肝癌细胞铁死亡，这为索拉非尼原发性耐药或继发性耐药的患者带来增敏治疗的可能。最后，研究发现HDAC1/HDAC2通过miRNAs调控了C/EBPalpha mRNA的稳定度，继而影响ACSL4的转录表达。本项课题研究一共资助培养了7位硕士研究生，发表了7篇SCI论文，3篇中文论文和1篇论著章节。研究期间，主持人和参与者参加了5次国际/国内会议并作口头和壁报演讲。本项课题研究结果有助于帮助理解肝癌的脂肪代谢重编程和其临床意义，并为肝癌患者的精准治疗提供了科学依据。

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