Molecular Functions of CDK1 in Gastric Tumorigenesis

CDK1在胃肿瘤发生中的分子功能

• 批准号: 10326393
• 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/10326393
• 关键词: Affect; Binding; Biological; Biology; CDC2 gene; Cancer Biology; Cancer Etiology; Cancer Model; Cancer Patient; Carcinogens; Cell Cycle; Cell Death; Cell Survival; Cells; Cessation of life; Cisplatin; Development; Diagnosis; Diagnostic; Epigenetic Process; Future; Genetic; Genetic Transcription; Growth; Helicobacter Infections; Helicobacter pylori; Human; Infection; Intervention; Link; Mediating; Molecular; Mus; NF-kappa B; Oncogenic; Oncology; Organoids; Outcome; Pathology; Persons; Pharmacology; Phosphorylation; Play; Population; Positioning Attribute; Preventive; Property; Refractory; Reporting; Resistance; Risk Factors; Role; Signal Pathway; Signal Transduction; Stimulus; Stomach; Stomach Carcinoma; Survival Rate; Technology; Therapeutic; Time; Tissue Sample; Transcriptional Regulation; United States; Work; base; cancer cell; cancer statistics; chemotherapeutic agent; chemotherapy; clinically significant; design; empowered; experience; gastric carcinogenesis; gastric tumorigenesis; genotoxicity; human tissue; improved; in vitro Model; malignant stomach neoplasm; mouse model; neoplastic cell; novel; novel therapeutic intervention; overexpression; prognostic; refractory cancer; response; self-renewal; therapy resistant; transcription factor; transcriptional reprogramming; 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/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 例新发病例，估计有 783,000 例 2018 年死亡人数。胃癌对治疗的反应较差，并且预后不良 估计总体5年生存率约为20%。癌细胞响应基因毒性刺激 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获得性适应性特性的发展，从而促进了生存 和肿瘤细胞的扩张。综合分析方法使我们能够从生物学角度识别 胃癌相关的新信号轴。我们在人类中检测到 CDK1 异常胞质过度表达 和小鼠胃癌。虽然 CDK1 是一种成熟的细胞周期调节因子，但我们之前发现 胃癌肿瘤细胞中未报道的功能，是该提案的重点。我们发现响应 对于遗传毒性刺激，例如感染和化疗，存活的肿瘤细胞池会发展出一种 获得适应性促生存反应，包括诱导 CDK1 和 SOX9 转录因子。我们 首次证明 CDK1 是响应 NF-kB 转录活性的激活而被诱导的。在 同时，CDK1 通过表观遗传机制诱导 SOX9，包括激活 DNMT1 和 miR-145 的抑制。通过遗传或药理学方法抑制 CDK1 会降低 SOX9 水平， 活性并诱导癌细胞死亡。基于新的初步结果，我们假设激活 CDK1-SOX9 轴响应幽门螺杆菌感染促进细胞存活和肿瘤细胞扩张 化疗干预。我们制定了三个具体目标，包括机械、功能、 使用体外模型、类器官培养物、小鼠模型和去识别的人体组织进行转化研究 样品。目标1，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。我们还将研究一种新的表观遗传联系，其中包括 CDK1 和 DNMT1 在调节中的作用。 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。翻译意义将在目标 3 中研究： 研究 CDK1-SOX9 功能轴在胃癌中的治疗潜力和临床意义。我们 组建了一支高度协作的团队，在先进分子技术、癌症 模型和肿瘤学使我们处于独特的地位来进行拟议的研究。完成此操作后 通过这项工作，我们期望推出一种新的 CDK1 和 SOX9 信号通路之间串扰的药物范式 在胃肿瘤的发生过程中。这些分子相互作用不仅提供了对生物学的新理解 胃癌，还为设计新的治疗干预措施提供未来的转化机会 胃癌。