Molecular Functions of CDK1 in Gastric Tumorigenesis

摘要/摘要：胃癌是全球第三大癌症相关死亡原因。2018年 全球癌症统计报告显示，估计新增病例超过100万例，估计为783,000例 2018年的死亡人数。胃癌对治疗的反应很差，预后不佳。 估计总的5年生存率约为20%。作为对基因毒性刺激的反应，癌细胞 经历转录和信号网络的重新连接和重新编程，以推动适应和生存 属性。这种重新编程导致获得性适应特性的发展，这些特性促进了生存 和肿瘤细胞的扩张。全面的分析方法使我们能够从生物学上识别 与胃癌相关的新信号轴。我们检测到人细胞内CDK1的异常过表达 和小鼠胃癌。虽然CDK1是一种公认的细胞周期调节因子，但我们之前已经发现 胃癌中肿瘤细胞的功能未见报道，这是本提案的重点。我们发现作为回应， 对遗传毒性刺激，如感染和化疗，存活的肿瘤细胞池发展成 获得性适应性促生存反应，包括CDK1和SOX9转录因子的诱导。我们 首次证明了CDK1是在核因子-kB转录活性激活时被诱导的。在… 与此同时，CDK1通过表观遗传机制诱导SOX9，包括激活DNMT1和 抑制miR-145。通过遗传或药物途径抑制CDK1可降低SOX9水平和 活性和诱导癌细胞死亡。根据新的初步结果，我们假设激活 CDK1-SOX9轴促进肿瘤细胞对幽门螺杆菌感染和 化疗干预。我们制定了三个具体目标，包括机械性、功能性、 以及使用体外模型、器官培养、小鼠模型和未识别的人体组织进行的翻译研究 样本。在目标1中，我们计划研究幽门螺杆菌感染和核因子-kB转录因子在调节 CDK1-SOX9轴。我们还将研究一种新的表观遗传学联系，它包括CDK1和DNMT1在调节 SOX9转录因子水平和活性。我们的第二个目标将集中在研究分子功能和 CDK1-SOX9轴的致癌转录网络翻译意义将在目标3中通过以下方式研究 探讨CDK1-SOX9功能轴在胃癌中的治疗潜力及临床意义。我们 已经组建了一个高度合作的团队，在先进的分子技术、癌症方面具有经验 模型和肿瘤学使我们处于执行拟议研究的独特位置。在完成此操作后 工作，我们希望揭示CDK1和SOX9信号通路之间的一种新的可用药的串扰范例 在胃肿瘤发生中的作用。这些分子间的相互作用不仅为我们提供了一种新的理解 但也为设计新的治疗干预措施提供了未来的翻译机会 胃癌。

ABSTRACT/SUMMARY: Gastric cancer is the third leading cause of cancer-related death worldwide. The 2018 global cancer statistics report indicates an estimated over 1,000,000 new cases and an estimated 783,000 deaths in 2018. Gastric cancers are poorly responsive to therapy and have an unfavorable outcome with an estimated overall 5-year survival rate of approximately 20%. In response to genotoxic stimuli, cancer cells undergo rewiring and reprogramming of transcription and signaling networks to drive adaption and survival properties. This reprogramming leads to the development of acquired adaptive properties that promote survival and expansion of neoplastic cells. Comprehensive analysis approaches have enabled us to identify a biologically relevant novel signaling axis in gastric cancer. We detected aberrant cytosolic overexpression of CDK1 in human and mouse gastric cancers. While CDK1 is a well-established cell cycle regulator, we have discovered previously unreported functions in neoplastic cells in gastric cancer, the focus of this proposal. We found that in response to genotoxic stimuli, such as infection and chemotherapeutics, the surviving pool of neoplastic cells develop an acquired adaptive pro-survival response that includes induction of CDK1 and SOX9 transcription factor. We demonstrate, for the first time, that CDK1 is induced in response to activation of NF-kB transcription activity. At the same time, CDK1 induces SOX9 through epigenetic mechanisms that include activation of DNMT1 and suppression of miR-145. Inhibition of CDK1 by genetic or pharmacologic approaches decreased SOX9 level and activity and induced cancer cell death. Based on novel preliminary results, we hypothesize that activation of CDK1-SOX9 axis promotes cell survival and expansion of neoplastic cells in response to H. pylori infection and chemotherapeutic interventions. We have developed three specific aims that include mechanistic, functional, and translational studies using in vitro models, organoid cultures, mouse models, and de-identified human tissue samples. In aim 1, we plan to investigate the role of H. pylori infection and NF-kB transcription factor in regulating CDK1-SOX9 axis. We will also investigate a novel epigenetic link that includes CDK1 and DNMT1 in regulating SOX9 transcription factor levels and activity. Our second aim will focus on investigating molecular functions and oncogenic transcription network of CDK1-SOX9 axis. The translational significance will be studied in aim 3 by investigating therapeutic potential and clinical significance of CDK1-SOX9 functional axis in gastric cancer. We have assembled a highly collaborative team with experience in advanced molecular technologies, cancer models, and oncology making us in a unique position to perform the proposed studies. Upon completion of this work, we expect to unveil a novel druggable paradigm of cross-talk between CDK1 and SOX9 signaling pathways in gastric tumorigenesis. These molecular interactions not only provide a novel understanding of the biology of gastric cancer but also offer future translational opportunities for the design of new therapeutic interventions for gastric cancer.