实体肿瘤中心癌细胞常处于能量缺乏等代谢应激状态，代谢应激耐受导致肿瘤进一步生长。本项目组已报道了卵泡抑素（FST）在能量缺乏耐受及细胞凋亡抑制中的重要作用，但其表达上调机制不明。前期预实验显示，mRNA稳定性调节蛋白AUF1可下调FST mRNA水平；抑制AUF1表达可减少能量缺乏诱导的细胞凋亡，提示AUF1可能通过调节FST 表达而参与肿瘤细胞能量稳态调节。为此，本项目将首先明确AUF1对FST mRNA降解的促进作用，确定FST mRNA上与AUF1结合的顺式作用元件；然后在细胞和动物水平研究AUF1在能量缺乏时肿瘤细胞凋亡中的作用，并探索AUF1对细胞凋亡的调节作用是否通过下调FST表达而实现；最后在结直肠癌组织中检测AUF1、FST蛋白表达及细胞内定位情况，评价其与结直肠癌发展的相关性。该项目研究将提高我们对肿瘤细胞能量稳态维持与肿瘤发展的认识，并可能为肿瘤治疗提供新靶点。

Solid tumors over a certain size are continuously exposed to metabolic stress microenvironment such as glucose deprivation. The cancer cells have to limit energy expenditure to survive under metabolic stress conditions. Follistatin (FST) has been demonstrated to participate in the maintenance of cancer cell energy homeostasis and protect cells against apoptosis. Glucose deprivation markedly enhanced the expression of FST with an unknown mechanism. Our previous studies have shown that knockdown of AUF1 increased FST mRNA level and decreased cell apoptosis, suggesting that AUF1 might participate in cellular energy homeostasis regulation by promoting FST mRNA decay. The goal of this project is to fully elucidate the role of AUF1-FST pathway in cancer cell adaptation to metabolic stress. First, we will consolidate the promoting effect of AUF1 on FST mRNA decay and identify the cis-element in FST mRNA. Next, we will define the role of AUF1 in energy deprivation-induced apoptosis using cell and mouse models. We will further investigate whether AUF1 execute its functions through regulating FST mRNA decay. Finally, we will establish the correlations between the expressions/localizations of AUF1/FST and tumor development in large-scale human colorectal cancer specimens. Completion of these studies will provide new insights into the role of AUF1-FST pathway in cancer cell metabolic stress tolerance and provide potential targets for cancer therapy.