LncRNA-PTCHD3P1/miR-9/NDRG2通过调节Warburg效应增敏肝癌多激酶抑制剂治疗并抑制肝癌生长及转移的研究

Recent studies showed that Warburg effect is associated with cancer chemosensitivity，and the multi-kinase inhibitors can increase the level of Warburg effect in liver cancer. However, whether lncRNAs has impact on Warburg effect and further affect chemosensitivity of multi-kinase inhibitors，proliferation and metastasis of liver cancer are still unknown. According to our earlier work, lncRNA-PTCHD3P1 is low-expressed in liver cancer，it inhibits Warburg effect significantly, enhances chemosensitivity of multi-kinase inhibitors in liver cancer and inhibits cell proliferation and metastasis in liver cncer；lncRNA-PTCHD3P1 up-regulated NDRG2 by competitively binding the miR-9；NDRG2 suppresses the expression of phosphofructokinase-1 (PFK-1; the key factor of glycolysis pathway). So we assume that lncRNA-PTCHD3P1 promotes NDRG2 expression by competitively binding the miR-9, and PFK-1 down-regulation inhibits the Warburg effect of liver cancer, finally enhances chemosensitivity of multi-kinase inhibitors in liver cancer and inhibits cell proliferation and metastasis in liver cncer. This subject will illuminate the mechanism of lncRNA-PTCHD3P1 pathway regulating liver cancer metabolism, and provide novel direction and idea for treatment of liver cancer from the new perspective of tumor metabolism.

Warburg效应与化疗敏感性相关，近期发现多激酶抑制剂能上调肝癌Warburg效应。LncRNAs是否可通过调控Warburg效应影响肝癌多激酶抑制剂治疗、增殖及转移尚属未知。课题组前期研究中发现lncRNA-PTCHD3P1在肝癌中低表达，lncRNA-PTCHD3P1可显著抑制Warburg效应，同时增敏肝癌多激酶抑制剂治疗并抑制肝癌的增殖和转移；lncRNA-PTCHD3P1可竞争性结合miR-9提高NDRG2的表达；NDRG2可以抑制糖酵解途径关键因子果糖磷酸激酶1的表达。因此，我们提出假设：lncRNA-PTCHD3P1通过抑制miR-9来提高NDRG2的表达，进而下调PFK-1来抑制肝癌的Warburg效应，从而增敏肝癌多激酶抑制剂治疗、抑制肝癌增殖和转移。本项目将阐明lncRNA-PTCHD3P1在肝癌代谢中的调控机制。从代谢这一全新角度为肝癌的治疗提供新的思路。

肝细胞癌是一种高死亡率的原发性肝癌，也是一种全球范围最常见的恶性肿瘤，其最重要的生物学特征是侵袭和转移。肿瘤细胞可以通过一种异常的糖代谢行为来逃避正常的细胞凋亡程序，增强增殖和迁徙能力，这种现象称为Warburg效应，是肿瘤得以发病的关键因素。我们之前的测序结果显示lncRNA-PTCHD3P1在肝癌中普遍低表达，并且与课题组之前研究的抑癌基因NDRG2的表达呈正相关，但是lncRNA-PTCHD3P1是否可通过调控NDRG2的表达，进而通过Warburg效应影响肝癌的增殖及转移尚属未知。在课题组本次研究中发现，lncRNA-PTCHD3P1主要定位于胞质中，在HCC组织和细胞系中高表达，并抑制肝癌的增殖和转移；lncRNA-PTCHD3P1可竞争性结合miR-9提高NDRG2的表达；NDRG2可以与抑制糖酵解途径关键因子果糖磷酸激酶1相结合抑制warburg效应。因此，我们得出结论：lncRNA-PTCHD3P1通过制miR-9来提高NDRG2的表达，进而下调PFK-1来抑制肝癌的Warburg效应，从而抑制肝癌增殖和转移。本项目将阐明lncRNA-PTCHD3P1在肝癌代谢中的调控机制，从代谢这一全新角度为肝癌的治疗提供新的思路。