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。

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.