AUF1调节卵泡抑素mRNA稳定性在肿瘤细胞代谢应激耐受中作用研究

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.

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。

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。我们前期预实验显示，卵泡抑素（FST）可抑制能量缺乏引起的细胞凋亡，提示其参与肿瘤细胞能量稳态调节。在此基础上，通过本项目研究发现：1）AUF1通过结合FST mRNA从而促进其降解；2）能量缺乏时AUF1与FST mRNA的结合减弱，导致FST mRNA水平升高；3）AUF1通过抑制FST表达发挥促肿瘤细胞凋亡作用；4）FST可促进结直肠癌细胞裸鼠体内成瘤。以上结果首次证明，AUF1抑制FST表达而调控能量应激引起的肿瘤细胞凋亡，成果发表在Nucleic Acids Res上。此外还发现：氧化应激可促进FST基因转录，成果发表在Sci Rep、Int J Biochem Cell Biol、Gene等杂志。临床样本分析发现：结直肠癌中FST低表达、AUF1高表达，且其表达与预后无相关性，这与预期不符。因此，AUF1/FST在结直肠癌发病中的临床意义仍有待深入研究。