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.

胃癌是世界上第五大常见恶性肿瘤，也是第三大致死性恶性肿瘤 在世界范围内，晚期的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）的分子靶向的关键 GC致癌过程中的事件。该应用是基于一个令人兴奋的发现，即具有villin启动子的小鼠- 驱动的PPAR-d过表达（villin-PPAR-d小鼠）自发地发展出大的和侵袭性的GC。我们 公开的数据显示PPAR-d在人GC组织中上调， 与患者预后不良有关。绒毛蛋白启动子在一小部分胃上皮细胞中有活性 被认为是绒毛蛋白阳性胃祖细胞（V-GPCs）的细胞。癌症干细胞（CSCs）被认为 来源于正常干/祖细胞的转化以驱动肿瘤形成。我们发现PPAR-d 增强V-GPC的干性，并通过激活PPAR-d-干扰素-使V-GPC形成肿瘤 γ（IFNG）信号环。此外，我们还发现：（1）CCL 20的上调最为显著， V-GPCs中PPAR-d过表达的趋化因子，和2）CCR 6 + CD 45+细胞（CCR 6是V-GPCs中PPAR-d过表达的唯一受体）。 CCL 20）的IFNG mRNA表达显著高于CCR 6-CD 45+细胞。幽门螺杆菌（H. pylori）是人类GC的I类致癌物。慢性H.幽门螺杆菌感染，目前影响近一半的 世界人口，是已知的人类GC的强风险因素。H.幽门螺杆菌感染增加PPAR-d，CCL 20， IFNG又促进了H.幽门诱导的胃炎症，增强GPCs的干性，并促进 小鼠和人的胃上皮细胞增殖。这种PPAR-d过度激活是否是H.幽门- 诱导的GC在很大程度上是未知的。解决这一知识差距对公众很重要，特别是对 患有慢性H.幽门螺杆菌感染，因为PPAR-d是一种可药用蛋白质， 已经开发了激动剂和拮抗剂，并且PPAR-d激动剂正用于非癌性疾病。 适应症（如增强肌肉耐力）。因此，我们假设GPCs中PPAR-d的过度激活 通过上调PPAR-d-CCL 20/CCR 6-IFNG信号通路和分子靶向该通路来驱动GC。 可能是一种新的GC干预模式。目的1将确定PPAR-d上调在 V-GPCs和Lgr 5-阳性GPCs（L-GPCs）在成年期对GC致癌作用的影响。目标2将决定效果 在H上V-GPCs或L-GPCs中PPAR-d基因缺失/功能丧失。猫诱导的GC肿瘤发生。H. felis是H. pylori感染小鼠的效果与H. pylori在人类目标3将 确定PPAR-d-IFNG信号传导失调的分子机制并评估 该通路的分子靶向对GC致癌作用的影响。我们希望这项提案的完成 不仅为胃癌的分子发病机制提供了新的见解，也将推动胃癌的发展。 用于GC预防和治疗的新机制方法。