Molecular Functions of CDK1 in Gastric Tumorigenesis

摘要/总结：胃癌是全球癌症相关死亡的第三大原因。2018年 全球癌症统计报告显示，估计有超过1，000，000例新病例， 2018年死亡。胃癌对治疗的反应性差，并且具有不利的结果， 估计5年生存率约为20%。为了应对基因毒性刺激，癌细胞 经历转录和信号网络的重新布线和重新编程，以驱动适应和生存 特性.这种重新编程导致了促进生存的后天适应性的发展 和肿瘤细胞的扩张。全面的分析方法使我们能够确定一种生物学上的 胃癌相关的新信号轴。我们检测到CDK 1在人类中的异常胞浆过表达， 和小鼠胃癌。虽然CDK 1是一种公认的细胞周期调节因子，但我们之前已经发现， 未报道的功能在胃癌的肿瘤细胞，重点是这个建议。我们发现， 对于遗传毒性刺激，如感染和化疗，存活的肿瘤细胞库发展成一种 获得性适应性促生存反应，包括诱导CDK 1和SOX 9转录因子。我们 第一次证明，CDK 1是响应于NF-κ B转录活性的激活而被诱导的。在 与此同时，CDK 1通过表观遗传机制诱导SOX 9，包括DNMT 1的激活和 抑制miR-145。通过遗传或药理学方法抑制CDK 1降低了SOX 9水平， 活性并诱导癌细胞死亡。基于新的初步结果，我们假设， CDK 1-SOX 9轴促进肿瘤细胞对H. hp感染与 化疗干预。我们已经制定了三个具体目标，包括机械，功能， 以及使用体外模型、类器官培养物、小鼠模型和去识别人类组织的转化研究 样品在目标1中，我们计划研究H。pylori感染与NF-κ B转录因子调控 CDK 1-SOX 9轴。我们还将研究一种新的表观遗传学联系，包括CDK 1和DNMT 1在调节 S 0X 9转录因子水平和活性。我们的第二个目标将集中于研究分子功能， CDK 1-SOX 9轴的致癌转录网络。翻译的意义将在目标3中研究， 探讨CDK 1-SOX 9功能轴在胃癌中的治疗潜力及临床意义。我们 组建了一个高度合作的团队，在先进的分子技术，癌症 模型和肿瘤学使我们在执行拟议研究方面处于独特的地位。在完成此 这项工作，我们希望揭示一种新的可药物化的CDK 1和SOX 9信号通路之间的串扰模式 在胃癌发生中的作用。这些分子间的相互作用不仅提供了一个新的理解的生物学， 同时也为设计新的治疗干预措施提供了未来的转化机会， 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.