乏糖刺激下FOXO1/LINC00461/HuR功能轴调控大肠癌糖酵解及恶性增殖的机制研究

The roles of long non-coding RNAs in cancer metabolism remain largely unexplored. In our previous study, we identified that LIN00461 was induced by FOXO1 activation under glucose deprivation. LINC00461 deficiency in colorectal cancer (CRC) cells alleviates energy stress-induced apoptosis. LINC00461 was significantly downregulated in CRC and markedly inhibits CRC proliferation in vitro and in vivo; Patients with lower LINC00461 expression levels had poorer prognosis. However, the real function of LINC00461 in CRC and the underlying regulatory mechanism still needs to be clarified. We show that LINC00461 deficiency leads to enhanced glucose uptake and lactate production through directly binding to HuR. There might be a FOXO1-LINC00461-HuR signaling pathway which plays an important role in CRC progression and adaption to energy stress. Based on these results, we proposed the potential mechanism hypothesis that under glucose deprivation, FOXO1-LINC00461-HuR signaling pathway activation inhibited CRC cell key enzymes in glycolysis, inducing adapative apoptosis. This project plans to investigate the biological function of LINC00461 in the development of CRC, and to clarify the mechanism of FOXO1-LINC00461-HuR signaling pathway in glycolysis and proliferation in CRC by using a series of biological experimental assays. The aims of this study is to offer new molecular markers for prognosis and targeted therapy of CRC.

长链非编码RNA（lncRNA）在肿瘤代谢中的作用机制仍有待探索。课题组前期结合lncRNA芯片发现乏糖刺激下FOXO1激活可上调LINC00461的表达，诱导细胞凋亡；LINC00461在大肠癌组织中下调且与患者预后相关，LINC00461过表达可抑制肿瘤细胞的体内外增殖能力及糖酵解过程；进一步研究发现LINC00461可通过HuR调控糖代谢关键酶的表达。基于以上结果，我们推测，大肠癌细胞内存在FOXO1/LINC00461/HuR功能轴，在乏糖刺激下被激活后，抑制细胞糖酵解，诱导细胞凋亡。本项目拟通过体内外生物学实验方法明确LINC00461在大肠癌中的功能并结合分子生物学实验阐明FOXO1/LINC00461/HuR功能轴在大肠癌糖酵解及恶性增殖中的分子机制，检测临床样本中该功能轴中关键分子的表达及与预后相关性，旨在为大肠癌预后评估提供新的分子标志物，为治疗提供新的靶点及思路。

长链非编码RNA(lncRNA)在肿瘤代谢中的作用机制仍有待探索。项目组前期结合lncRNA 芯片发现乏糖刺激下FOXO1激活可上调LINC00461的表达，且可能通过HuR调控葡萄糖代谢及细胞增殖。本项目主要探索了乏糖刺激下FOXO1/LINC00461/HuR功能轴调控大肠癌糖酵解及恶性增殖的机制研究。项目主要完成了以下研究内容：(1)乏糖激活FOXO1上调LINC00461诱导细胞凋亡；(2)LINC00461调控大肠癌细胞糖酵解及恶性增殖；(3)LINC00461 通过HuR调控大肠癌细胞增殖及糖酵解；(4)FOXO1/LINC00461/HuR功能轴中关键分子与大肠癌患者预后及肿瘤能量代谢之间的相关性。我们的项目基本明确乏糖刺激下FOXO1诱导LINC00461表达上调的分子机制；初步揭示LINC00461/HuR功能轴在大肠癌恶性增殖及糖酵解过程中的分子调控机制；探讨FOXO1/LINC00461/HuR功能轴在大肠癌预后判断中的临床应用价值，为大肠癌的预防和治疗提供新的思路。