钾通道Kir2.1逆转PUM1功能表观调控胃癌干细胞多药耐药的机制研究

多药耐药是胃癌化疗失败的主要原因，胃癌干细胞是胃癌多药耐药产生的细胞学基础，但调控机制不清。我们在既往研究中发现钾通道Kir2.1是促进胃癌侵袭转移的重要分子，同时还发现其在胃癌组织中的表达水平与患者化疗后的预后显著相关。进一步的研究表明，Kir2.1在胃癌干细胞中高表达，促进胃癌干细胞多药耐药产生，且该作用不依赖其通道功能，而与Sox2有关。深入研究发现，Kir2.1能与PUM1相互作用，文献报道PUM1能促进mRNA降解，且Sox2的mRNA上有PUM1的结合位点。据此，我们推测Kir2.1可能通过与PUM1 相互作用而抑制PUM1对Sox2 mRNA的降解，增加Sox2表达，进而促进多药耐药相关分子表达而诱发胃癌干细胞多药耐药产生。本研究拟用胃癌干细胞及临床标本为材料，采用多种分子生物学技术和体内外实验探索Kir2.1在胃癌干细胞多药耐药中的作用和机制，为逆转胃癌多药耐药提供新靶标。

In gastric cancer, multidrug resistance is the main reason of chemotherapy failure and gastric cancer stem cells are the cytological basis for multidrug resistance, but the regulatory molecular mechanism is unclear. In our previous studies, we have found that the inward rectifier potassium channel 2.1 (Kir2.1) is a pro-malignant factor in invasion and metastasis of gastric cancer, and also found that its expression level in gastric cancer tissues was significantly correlated with the prognosis of chemotherapy patients. Further studies showed that Kir2.1 was highly expressed in gastric cancer stem cells and induced multidrug resistance of gastric cancer stem cells. Preliminary mechanism research showed that Kir2.1 contributed to multidrug resistance by a non-canonical ion permeation-independent signaling pathway, and related to Sox2. Further studies found that Kir2.1 could interact with PUM1, while reports showed that PUM1 can promote the degradation of mRNA and the binding site of PUM1 on Sox2 mRNA. Based on this, we hypothesized that Kir2.1 may inhibit the PUM1-related degradation of Sox2 mRNA through interaction with PUM1, increase the expression of Sox2, and promote the expression of multidrug resistance-related molecules, then induce multidrug resistance of gastric cancer stem cells. In this study, we intend to employ gastric cancer stem cells and clinical specimens for materials, using a variety of molecular biology techniques and in vitro and in vivo experiments to explore the function and molecular mechanism of Kir2.1 in multidrug resistance of gastric cancer stem cells. It is expected to provide new targets for reversing multidrug resistance of gastric cancer.