晚期胃癌患者的生存期短，对化疗和已有的靶向药物反应性不佳，因此寻找有效的新型靶点是突破治疗瓶颈的重要方式。细胞周期依赖性激酶8（CDK8）在胃癌中呈现高表达，然而其在胃癌进展中的具体作用尚不清楚。本课题组前期实验发现CDK8敲除可显著抑制胃癌细胞增殖、侵袭等恶性表型。同时，CDK8敲除后，Cyclin D1的磷酸化水平降低，Cyclin D1下游具有抑癌作用的NRF1表达上调，提示Cyclin D1为CDK8的全新下游，CDK8敲除可减弱Cyclin D1活性从而解除其对NRF1的抑制作用。因此我们提出假说：CDK8通过直接磷酸化Cyclin D1的方式活化Cyclin D1-NRF1信号通路从而促进胃癌进展。在预实验的基础上，本课题将通过体内外实验阐明CDK8在胃癌进展中的作用及调控机制，同时进一步探讨应用CDK8抑制剂治疗胃癌的可行性，旨在为晚期胃癌的靶向治疗提供新思路。

Exploring novel and efficient therapeutic targets of late-stage gastric cancer is in an urgent need due to its limited response to current treatment regimens. Cyclin-dependent kinase 8 (CDK8) is a serine/threonine kinase that is highly expressed in several cancer types. However, its role in gastric cancer progression is still unclear. Our preliminary data showed that CDK8 depletion in gastric cancer cells significantly suppressed proliferation, migration, invasion, colony formation and tumor growth in nude mice. Interestingly, we found upon CDK8 knockout, the phosphorylation of oncoprotein Cyclin D1 was greatly inhibited and the expression of NRF1，which is tumor-suppressive and a downstream target of Cyclin D1，was obviously improved. Thus, we hypothesize that CDK8 promotes gastric cancer progression through Cyclin D1 phosphorylation and subsequently NRF1 inhibition, which could be a novel target for gastric cancer therapy. In this study, we will for the first time elucidate the role of CDK8 and the specific molecular mechanism that CDK8 regulates Cyclin D1-NRF1 signaling axis in gastric cancer progression, and we will also evaluate the effect of CDK8 inhibitor (Senexin B) in mouse models, which aims to provide the new evidence and strategy for the targeted therapy of gastric cancer.