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

基本信息

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
项目类别：
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

项目摘要

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）是第五大常见恶性肿瘤和第三大致命癌症在全球范围内，晚期患者的 5 年生存率为 5-10%。我们研究的长期目标是基于关键的分子靶向开发新的干预措施来预防和治疗胃癌（GC）该应用基于一项令人兴奋的发现，即具有绒毛启动子的小鼠– 驱动的 PPAR-d 过度表达（villin-PPAR-d 小鼠）自发形成大型侵袭性 GC。已发表的数据表明，PPAR-d 在人 GC 组织中上调，并且这种上调是 Villin 启动子在胃上皮的一小部分亚群中活跃。被认为是绒毛阳性胃祖细胞（V-GPC）的细胞被认为是癌症干细胞（CSC）。我们发现 PPAR-d 是由正常干/祖细胞转化驱动肿瘤形成而产生的。增强V-GPCs的干性，并通过激活PPAR-d-干扰素-使V-GPCs形成肿瘤此外，我们还发现 1) CCL20 上调最显着。 V-GPC 中 PPAR-d 过表达导致趋化因子，2) CCR6+CD45+ 细胞（CCR6 是趋化因子的唯一受体） CCL20) 的 IFNG mRNA 表达显着高于幽门螺杆菌 (H. pylori) CCR6-CD45+ 细胞。 pylori）是人类慢性幽门螺杆菌感染的 I 类致癌物，目前影响着近一半的人。世界人口中，已知幽门螺杆菌感染会增加 PPAR-d、CCL20 和 GC 的强烈危险因素。 IFNG 反过来促进幽门螺杆菌诱导的胃炎症，增强 GPC 的干性并促进小鼠和人类的胃上皮增殖是否是幽门螺杆菌所必需的 PPAR-d 过度激活—— 引起的 GC 在很大程度上是未知的，解决这一知识空白对公众来说很重要，尤其是对于公众来说。患有慢性幽门螺杆菌感染的个体，因为 PPAR-d 是一种可药物蛋白，激动剂和拮抗剂已被开发出来，PPAR-d 激动剂正用于治疗非癌因此，我们研究了 GPC 中 PPAR-d 的过度激活。通过上调 PPAR-d–CCL20/CCR6–IFNG 信号通路和分子靶向来驱动 GC 途径可能是 GC 的一种新干预方式，目标 1 将确定 PPAR-d 上调在 GC 中的作用。成人发病时的 V-GPC 和 Lgr5 阳性 GPC (L-GPC) 对 GC 癌变的影响将决定目标 2。 V-GPC 或 L-GPC 中 PPAR-d 基因缺失/功能丧失对猫嗜血杆菌诱导的 GC 肿瘤发生的影响。猫科动物是幽门螺杆菌的近亲，它对小鼠的作用与幽门螺杆菌对人类的作用类似。确定 PPAR-d-IFNG 信号传导失调的分子机制并评估我们期望该提案能够完成该通路的分子靶向作用。不仅将为GC的分子发病机制提供新的见解，而且将促进GC的发展基于机制的GC预防和治疗新方法。