锌离子转运体SLC39A10通过激活CK2介导的MAPK/ERK和PI3K/AKT信号通路促进胃癌进展的机制研究

Gastric cancer is a common malignant tumor in the digestive system, and is highly prevalent in China with poor prognosis. Zinc transporter SLC39A10 is involved in the process of zinc ion transport into cells, and has been demonstrated to be overexpressed in different types of cancer; however, its role in gastric cancer remains unclear. Our preliminary data showed that SLC39A10 was significantly up-regulated in gastric cancer tissues compared to non-cancerous gastric tissues, and found that increased expression of SLC39A10 was strongly associated with poor patient survival. Functional studies showed that SLC39A10 significantly promoted malignant phenotype of gastric cancer cells, such as cell proliferation, colony formation, migration and invasion, indicating that SLC39A10 may be a potential oncogene in gastric cancer. In addition, we found that ectopic expression of SLC39A10 increased Zn2+ concentration in the cytoplasm of gastric cancer cells, and upregulated phosphorylation levels of ERK and AKT. Notably, Zn2+ chelator could effectively reverse tumor-promoting role of SLC39A10. Thus, we speculate that SLC39A10 activates the MAPK/ERK and PI3K/AKT pathways through regulating the activity of CK2, which is highly structurally dependent on Zn2+, thereby promoting malignant progression of gastric cancer cells. Based on these findings, the aims of this project were to further clarify the biological function of SLC39A10 in gastric cancer, and explore the molecular mechanism of SLC39A10 promoting gastric tumorigenesis through regulating intracellular zinc homeostasis through a series of in vitro and in vivo experiments, thereby providing a potential therapeutic target and prognostic biomarker for gastric cancer patients.

胃癌是消化系统常见的恶性肿瘤，发病率高，预后差，其发病机制仍不明确。SLC39A10参与调控Zn2+转运，在多种恶性肿瘤中表达升高。课题组前期结果显示，相较于癌旁组织，SLC39A10在胃癌组织中显著上调，且高表达的SLC39A10与患者的不良预后相关。功能实验证实SLC39A10可促进胃癌细胞的增殖、克隆形成、迁移、侵袭等恶性行为，增加细胞内Zn2+浓度，上调ERK和AKT的磷酸化水平。同时，我们也发现Zn2+螯合剂可有效逆转其促癌作用。根据上述结果，我们推测SLC39A10可通过调控Zn2+高度依赖的激酶CK2的活性，激活其下游MAPK/ERK和PI3K/AKT信号通路促进胃癌的进展。本项目旨在此基础上通过一系列体内外实验完善SLC39A10在胃癌中的生物学功能，阐明其通过调节胞内锌稳态促进胃癌恶性进展的分子机制，为胃癌的治疗提供潜在的靶点，为患者的预后评估提供分子标志物。

研究背景：胃癌是一种常见的消化道恶性肿瘤，目前缺乏早期发现胃癌的有效筛查手段。.SLC39A10（ZIP10）属于溶质载体家族成员，参与Zn2+的跨膜转运，有报道称上调SLC39A10可促进乳腺癌的转移。但是其在胃癌中的作用和机制尚不清楚。.研究目的：检测SLC39A10在胃癌组织和癌旁组织中的表达水平，分析其与预后的相关性；探索SLC39A10对胃癌恶性生物学行为的影响；鉴定SLC39A10在胃癌中调控的信号通路，揭示分子机制。.实验方法：.1）检测胃癌组织和癌旁组织中SLC39A10的表达水平。.2）明确SLC39A10对胃癌细胞增殖及克隆形成能力、周期分布及细胞凋亡、转移及体内成瘤能力的影响。.3）揭示SLC39A10通过调控胞内Zn2+稳态、影响CK2酶结构和活性，参与胃癌恶性进展的分子机制。.4）明确转录因子c-Myc对SLC39A10基因的转录调控作用。.实验结果：.1）相较癌旁组织，SLC39A10在胃癌组织中表达明显升高，与胃癌患者的不良预后相关。.2）敲减SLC39A10能抑制胃癌细胞的增殖、克隆形成及体内的成瘤能力；相反，过表达SLC39A10则增强胃癌细胞的恶性行为；.3）SLC39A10影响胃癌细胞内锌稳态，使细胞内CK2的酶活性和蛋白稳定性增加，进而激活MAPK/ERK和PI3K/AKT信号通路； .4）SLC39A10增强胃癌细胞中c-Myc的表达，同时c-Myc可以在转录水平上调SLC39A10的表达，形成正反馈环路促进胃癌进展。.结论：.研究证实在胃癌组织中SLC39A10高表达，与胃癌患者的不良预后相关。SLC39A10通过影响锌稳态，增加CK2的酶活性和蛋白稳定性，进而激活MAPK/ERK和PI3K/AKT信号通路；同时SLC39A10与c-Myc形成正反馈环路促进胃癌的恶性进展。

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