Molecular Functions of CDK1 in Gastric Tumorigenesis

CDK1在胃肿瘤发生中的分子功能

• 批准号: 10546490
• 负责人: WAEL EL-RIFAI
• 金额: $ 45.4万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-12 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10546490
• 关键词: Affect; Binding; Biological; Biology; CDC2 gene; Cancer Biology; Cancer Etiology; Cancer Model; Cancer Patient; Carcinogens; Cell Cycle; Cell Death; Cell Death Induction; Cell Survival; Cells; Cessation of life; Cisplatin; Development; Diagnosis; Diagnostic; Epigenetic Process; Future; Genetic; Genetic Transcription; Growth; Helicobacter Infections; Helicobacter pylori; Human; Infection; Link; Mediating; Molecular; Mus; NF-kappa B; Oncogenic; Oncology; Organoids; Outcome; Pathology; Persons; Phosphorylation; Play; Population; Positioning Attribute; Preventive; Property; Refractory; Reporting; Resistance; Risk Factors; Role; Signal Pathway; Signal Transduction; Stimulus; Stomach Carcinoma; Survival Rate; Technology; Therapeutic; Therapeutic Intervention; Time; Tissue Sample; Transcriptional Regulation; United States; Work; cancer cell; cancer statistics; carcinogenesis; chemotherapeutic agent; chemotherapy; clinically significant; design; empowerment; experience; gastric carcinogenesis; gastric tumorigenesis; genotoxicity; human tissue; improved; in vitro Model; malignant stomach neoplasm; mouse model; neoplastic cell; novel; novel therapeutic intervention; overexpression; pharmacologic; prognostic; refractory cancer; response; self-renewal; therapy resistant; transcription factor; transcriptional reprogramming; translational potential; translational study

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.

摘要/摘要：胃癌是全球与癌症相关死亡的第三大主要原因。 2018年 全球癌症统计报告表明，估计有1,000,000个新病例，估计有783,000例 2018年的死亡。胃癌对治疗的反应不佳，并且结果不利 估计总体5年生存率约为20％。响应遗传毒性刺激，癌细胞 进行转录和信号网络的重新布线和重编程以驱动适应和存活 特性。这种重编程会导致获得的自适应特性的发展，从而促进生存 和肿瘤细胞的扩展。全面的分析方法使我们能够在生物学上识别 相关的新型信号轴胃癌。我们检测到人类CDK1的异常胞质过表达 和小鼠胃癌。虽然CDK1是一个完善的细胞周期调节器，但我们之前已经发现 该提案的重点是胃癌的肿瘤细胞中未报告的功能。我们发现是为了回应 对于遗传毒性刺激，例如感染和化学治疗剂，存活的肿瘤细胞会发展 获得的自适应促生存反应，包括诱导CDK1和SOX9转录因子。我们 首次证明CDK1是响应NF-KB转录活性的激活而诱导的。在 同时，CDK1通过表观遗传机制诱导SOX9，包括激活DNMT1和 抑制miR-145。通过遗传或药理方法抑制CDK1的抑制作用降低了SOX9水平， 活性和诱发癌细胞死亡。基于新的初步结果，我们假设激活 CDK1-SOX9轴促进了幽门螺杆菌感染和肿瘤细胞的生存和膨胀 化学治疗干预措施。我们开发了三个特定目标，包括机械，功能， 以及使用体外模型，器官培养物，小鼠模型和去识别的人体组织的翻译研究 样品。在AIM 1中，我们计划研究幽门螺杆菌感染和NF-KB转录因子在调节中的作用 CDK1-SOX9轴。我们还将调查一个新的表观遗传链接，其中包括CDK1和DNMT1在调节中 SOX9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和 CDK1-SOX9轴的致癌转录网络。翻译意义将在AIM 3中研究 研究CDK1-SOX9功能轴对胃癌的治疗潜力和临床意义。我们 已经组建了一个高度协作的团队，该团队具有高级分子技术，癌症的经验 模型和肿瘤学使我们处于执行拟议研究的独特位置。完成此任务后 工作，我们期望揭示CDK1和SOX9信号通路之间的新型可毒品范围 在胃肿瘤发生中。这些分子相互作用不仅提供了对生物学的新了解 胃癌，但还为设计新的治疗干预措施提供了未来的翻译机会 胃癌。