Molecular Understanding and Targeting of Determinant Factors in Gastric Tumorigenesis

胃肿瘤发生决定因素的分子理解和靶向

• 批准号: 10619537
• 负责人: Xiangsheng Zuo
• 金额: $ 36.32万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619537
• 关键词: Address; Adenocarcinoma; Adult; Advanced Development; Affect; Agonist; Breeding; CCL20 gene; CCR6 gene; Carcinogens; Cell Lineage; Cell Separation; Cells; Chronic; Coculture Techniques; Data; Development; Enterobacteria phage P1 Cre recombinase; Epithelial Cells; Epithelium; Event; Exposure to; Flow Cytometry; Gastric Tissue; Gastritis; Genes; Genetic; Goals; Harvest; Helicobacter Infections; Helicobacter felis; Helicobacter pylori; Helicobacter pylori induced gastric cancer; Histologic; Human; IFNGR1 gene; Immune; In Vitro; Incidence; Individual; Infiltration; Inflammation; Interferon Type II; Internal Ribosome Entry Site; Intervention; Knockout Mice; Knowledge; LGR5 gene; Malignant Neoplasms; Methylnitrosourea; Migration Assay; Modality; Molecular; Molecular Target; Mus; Muscle; PPAR delta; PTPRC gene; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Population; Process; Production; Proliferating; Protein Sortings; Proteins; Publishing; Reporter Genes; Research; Risk Factors; Rodent; Role; Signal Pathway; Signal Transduction; Sorting; Stomach; Stomach Neoplasms; Survival Rate; Tamoxifen; Testing; Time; Tissues; Transgenic Organisms; Tumor-infiltrating immune cells; Up-Regulation; antagonist; cancer prevention; cancer stem cell; cancer therapy; carcinogenesis; chemokine; delta protein; experimental study; gastric cancer prevention; gastric corpus; gastric tumorigenesis; insight; loss of function; mRNA Expression; malignant stomach neoplasm; mouse model; negative affect; novel; novel therapeutics; overexpression; patient prognosis; prevent; progenitor; promoter; receptor; red fluorescent protein; single-cell RNA sequencing; stem cell proliferation; stem cells; stemness; tumor; tumorigenesis; villin

ABSTRACT Gastric cancer (GC) is the fifth most common malignancy and the third most lethal cancer worldwide, with a 5-year survival rate of 5-10% in advanced stages. The long-term goal of our research is to develop novel interventions to prevent and treat gastric cancer (GC) based on molecular targeting of crucial events in GC carcinogenesis. This application is based on an exciting finding that mice with villin-promoter– driven PPAR-d overexpression (villin-PPAR-d mice) spontaneously developed large and invasive GCs. Our published data showed that PPAR-d was upregulated in human GC tissues and this upregulation was associated with poor prognosis of patients. Villin promoter is active in a small subpopulation of gastric epithelial cells that are considered villin-positive gastric progenitor cells (V-GPCs). Cancer stem cells (CSCs) are thought to arise from transformation of normal stem/progenitor cells to drive tumor formation. We found that PPAR-d enhanced the stemness of V-GPCs and enabled V-GPCs to form tumors via activating the PPAR-d–interferon- gamma (IFNG) signaling loop. Furthermore, we also found 1) CCL20 is the most markedly upregulated chemokine by PPAR-d overexpression in V-GPCs, and 2) CCR6+CD45+ cells (CCR6 is the sole receptor of CCL20) have significantly higher IFNG mRNA expression than CCR6-CD45+ cells do. Helicobacter pylori (H. pylori) is a class I carcinogen for human GC. Chronic H. pylori infection, currently affecting nearly half of the world population, is a known strong risk factor for human GC. H. pylori infection increases PPAR-d, CCL20, and IFNG, which in turn promotes H. pylori–induced gastric inflammation, enhances GPCs’ stemness and promotes gastric epithelial proliferation in mice and humans. Whether this PPAR-d overactivation is required for H. pylori– induced GC is largely unknown. Addressing this knowledge gap is important to the public, especially for individuals who suffer from chronic H. pylori infection, because PPAR-d is a druggable protein for which both agonists and antagonists have been developed, and PPAR-d agonists are being used for noncancerous indications (e.g. enhancing muscle endurance). Thus, we hypothesize that PPAR-d overactivation in GPCs drives GC via upregulating the PPAR-d–CCL20/CCR6–IFNG signaling pathway and molecular targeting of this pathway could be a novel intervention modality for GC. Aim 1 will determine the role of PPAR-d upregulation in V-GPCs and Lgr5-positive GPCs (L-GPCs) at adult onset on GC carcinogenesis. Aim 2 will determine the effect of PPAR-d genetic deletion/loss of function in V-GPCs or L-GPCs on H. felis-induced GC tumorigenesis. H. felis is a close relative of H. pylori that has analogous effects in mice to those of H. pylori in humans. Aim 3 will determine the molecular mechanisms underlying dysregulated PPAR-d–IFNG signaling and evaluate the effects of molecular targeting of this pathway on GC carcinogenesis. We expect that completion of this proposal will not only provide new insights into the molecular pathogenesis of GC, but also advance the development of novel mechanism-based approaches for GC prevention and therapy.

摘要胃癌（GC）是第五大最常见的恶性肿瘤，也是第三大致命癌症 在全球范围内，高级阶段的5年生存率为5-10％。我们研究的长期目标是 开发新的干预措施，以预防和治疗胃癌（GC）基于关键的分子靶向 GC癌变中的事件。该应用程序是基于一个令人兴奋的发现，即与Villin启动器的老鼠 - 驱动的PPAR-D过表达（Villin-Ppar-D小鼠）发起了大型和侵入性的GC。我们的 发布的数据显示，PPAR-D已在人类GC组织中进行了更新，此更新是 与患者预后不良有关。 Villin启动子活跃于胃上皮的少量亚群中 被认为是villin阳性胃祖细胞（V-GPC）的细胞。癌症干细胞（CSC）被认为 正常的茎/祖细胞转化以驱动肿瘤形成。我们发现PPAR-D 增强了V-GPC的干性，并使V-GPC通过激活PPAR-D-插齿形成肿瘤 伽玛（IFNG）信号循环。此外，我们还发现1）CCL20是最明显的更新 PPAR-D在V-GPC中的趋化因子和2）CCR6+ CD45+细胞（CCR6是唯一的接收器 CCL20的IFNG mRNA表达明显高于CCR6-CD45+细胞所做的。幽门螺杆菌（H.） 幽门螺杆菌是人类GC的I类致癌。慢性幽门螺杆菌感染，目前几乎影响一半 世界人口是人类GC的已知强大风险因素。幽门螺杆菌感染增加了PPAR-D，CCL20和 IFNG又促进幽门螺杆菌诱导的胃感染，增强了GPC的茎并促进 小鼠和人类的胃上皮增殖。幽门螺杆菌 - 是否需要这种PPAR-D过度活化 诱导的GC在很大程度上未知。解决这一知识差距对公众很重要，尤其是对 患有慢性幽门螺杆菌感染的个体，因为PPAR-D是一种可吸毒的蛋白质 激动剂和拮抗剂已经开发出来，PPAR-D激动剂被用于非癌症 适应症（例如增强肌肉耐力）。那我们假设GPC中的PPAR-D过度活化 通过上调PPAR-D – CCL20/CCR6 – IFNG信号通路和分子靶向驱动GC 途径可能是GC的新型干预方式。 AIM 1将确定PPAR-D上调的作用 GC癌变成人发作时的V-GPC和LGR5阳性GPC（L-GPC）。 AIM 2将决定效果 felis诱导的GC肿瘤发生的V-GPCS或L-GPC中PPAR-D遗传缺失/功能丧失。 H. Felis是幽门螺杆菌的近亲，在小鼠中与人类幽门螺杆菌的小鼠具有类似的作用。目标3意志 确定PPAR-D-ifng信号失调的分子机制，并评估 该途径分子靶向对GC癌变的影响。我们预计该提议的完成 不仅将为GC的分子发病机理提供新的见解，还可以推进 基于新型机制的预防和​​治疗方法。