SLC5A3介导的肌醇转运对胰腺癌进展及肿瘤细胞糖酵解的作用与机制研究

Multiple recent studies have shown that tumor cell metabolism plays a pivotal role in the progression of pancreatic cancer. Our previous studies found that the content of myo-inositol in pancreatic cancer tissue was significantly increased than that in adjacent tissue, and further confirmed that the aberrant high expression of inositol transporter SLC5A3 in pancreatic cancer was the main reason for the increase of inositol. Cell experiments showed that SLC5A3 had an effect on the proliferation, apoptosis of pancreatic cancer cells by transporting inositol into tumor cell, and could significantly improve the cell's glycolysis ability. We further found that inositol promoted the glycolysis ability mainly depending on the increase of its downstream metabolite phosphatidylinositol PIP3, and PIP3 could promote Akt phosphorylation and activate its downstream glycolysis-related signaling pathway, thereby promoting the development of pancreatic cancer. In addition, we also found that up-regulation of SLC5A3 in the pancreatic cancer-specific hypoxic microenvironment relied on the regulation of the transcription factor NFAT5. Next, our study will further investigate the regulation of SLC5A3 expression and the molecular mechanism of promoting glycolysis, and explore the inhibitory effect of myo-inositol antagonist on the function of SLC5A3, so as to deepen our understanding of the biological characteristics of pancreatic cancer and provide new ideas for its treatment.

近年来的大量研究表明，肿瘤细胞代谢的改变处于胰腺癌发生进展的中心环节。在前期工作中，我们发现肌醇在胰腺癌组织中的含量显著高于癌旁组织，并进一步证实肌醇转运体SLC5A3在胰腺癌中的异常高表达是肌醇含量上升的主要原因。细胞实验表明，SLC5A3通过转运肌醇到肿瘤细胞内对胰腺癌细胞的增殖、凋亡均有影响，并能显著提高细胞的糖酵解能力。同时我们发现肌醇促进肿瘤细胞的糖酵解能力主要依赖其下游代谢物磷脂酰肌醇PIP3含量的上升，PIP3能够促进Akt磷酸化并激活其下游糖酵解相关信号通路，进而发挥了促进胰腺癌发展的作用。另外，我们还发现SLC5A3在胰腺癌的上调依赖于转录因子NFAT5的调控。接下来本课题将进一步研究SLC5A3的表达调控及促进糖酵解的分子机制，并探讨SLC5A3抑制剂根皮苷对SLC5A3功能的抑制作用，以期通过我们的研究加深对胰腺癌生物学特征的认识并为其治疗提供新的思路。

近年来的大量研究表明，肿瘤细胞代谢的改变处于胰腺癌发生进展的中心环节。在前期工作中，我们发现肌醇在胰腺癌组织中的含量显著高于癌旁组织，并进一步证实肌醇转运体SLC5A3在胰腺癌中的异常高表达是肌醇含量上升的主要原因。细胞实验表明，SLC5A3通过转运肌醇到肿瘤细胞内对胰腺癌细胞的增殖、凋亡均有影响，并能显著提高细胞的糖酵解能力。同时我们发现肌醇促进肿瘤细胞的糖酵解能力主要依赖其下游代谢物磷脂酰肌醇PIP3含量的上升，PIP3能够促进AKT磷酸化并激活其下游糖酵解相关信号通路，进而发挥了促进胰腺癌发展的作用。接下来本课题将进一步研究SLC5A3的表达调控及促进糖酵解的分子机制，并探讨SLC5A3抑制剂根皮苷对SLC5A3功能的抑制作用，以期通过我们的研究加深对胰腺癌生物学特征的认识并为其治疗提供新的思路。