Opisthorchis Viverrini ES Proteins and the Tumorgenic Environment

Opisthorchis Viverrini ES 蛋白和致瘤环境

基本信息

批准号：
8919230
负责人：
Thewarach Laha
金额：
$ 10.09万
依托单位：
KHON KAEN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8919230
关键词：
Address Anthelmintics Apoptosis Apoptotic Area Bile Duct Epithelium Bile duct carcinoma Binding Cancer Etiology Cancerous Carcinogens Cell Line Cell Proliferation Cells Cessation of life Cholangiocarcinoma Chronic Country Cutaneous DNA Damage Development Diet Ecology Environment Epithelium Exhibits Fasciola hepatica Fibroblasts Fishes Growth Factor Hamsters Health education Homologous Gene Human In Vitro Incidence Infection Inflammation International Agency for Research on Cancer Intervention Laos Link Malignant Neoplasms Malignant neoplasm of liver Mammalian Cell Mitosis Modeling Molecular Mus Neoplasm Metastasis New York Opisthorchiasis Opisthorchis viverrini Parasites Pathogenesis Pathology Pharmaceutical Preparations Physiological Praziquantel Prevalence Process Proliferating Property Protein Secretion Proteins Public Health Punch Biopsy Recombinants Reporting Research Role Route Secretory Component Thailand Time Trematoda Vaccinated Work World Health Organization Wound Healing bile duct biliary tract carcinogenesis carcinogenicity cholangiocyte disorder control granulin in vivo migration outcome forecast parasitism pathogen secretory protein thioredoxin peroxidase tumor tumorigenesis tumorigenic uncooked vaccine trial

项目摘要

The research deals with cholangiocarcinoma (CCA), bile duct cancer, caused by infection with the liver fluke, Opisthorchis viverrini. CCA is a primary cancer originating in the epithelium (cholangiocytes) ofthe bile ducts. It has long latency, is invasive, metastasizes and has a dismal prognosis. The mechanisms by which chronic infection with the flukes results in CCA are likely multi-factorial, but one mechanism is the secretion of parasite proteins with mitogenic and anti-apoptotic properties, both features of a pre-cancerous cellular environment. We have characterised the excretory/secretory (ES) products of O. viverrini and identified two candidate ES proteins that are central to these processes - we showed that a homologue of the human secreted growth factor, granulin, binds to cholangiocytes and stimulates proliferation of fibroblasts and CCA cell lines. We also showed that secreted thioredoxin peroxidase blocks apoptosis of damaged cholangiocytes. Progression of chronic opisthorchiasis to CCA follows a multi-factorial route(s). We hypothesize that key processes along the route include (1) secretion of parasite proteins which induce pathology in the biliary tract and establish an environment conducive to cancer development by promoting cell proliferation and DNA damage, accelerating wound healing and blocking apoptosis; and (2) repeated administration of the anthelmintic drug praziquantel, for treatment of O. viverrini (Ov) infection, causes increased inflammation in the bile ducts and thereby precipitates tumorigenesis. The research will investigate these phenomena by assessing the ability of Ov-ES to (1) facilitate wound repair in mammalian cells; (2) promote cell invasion and migration; (3) interfere with apoptosis. To further address the carcinogenic roles of these proteins, we will vaccinate hamsters with Ov-ES and its defined components to determine whether this intervention can protect against liver fluke infection and CCA, and assessment of impact of repeated PZQ therapy in accelerating tumorigenesis.

该研究涉及胆管癌（CCA），即由肝吸虫 Opisthorchis viverrini 感染引起的胆管癌。 CCA 是一种起源于胆管上皮（胆管细胞）的原发性癌症。它潜伏期长、具有侵袭性、易转移且预后较差。吸虫慢性感染导致 CCA 的机制可能是多因素的，但其中一种机制是分泌具有促有丝分裂和抗凋亡特性的寄生虫蛋白，这都是癌前细胞环境的特征。我们对 O. viverrini 的排泄/分泌 (ES) 产物进行了表征，并鉴定了对这些过程至关重要的两种候选 ES 蛋白 - 我们表明，人类分泌生长因子颗粒蛋白的同源物与胆管细胞结合并刺激成纤维细胞增殖和CCA细胞系。我们还表明，分泌的硫氧还蛋白过氧化物酶可阻止受损胆管细胞的凋亡。慢性后睾丸病进展为 CCA 遵循多因素途径。我们假设该途径的关键过程包括（1）分泌寄生虫蛋白，诱导胆道病理并通过促进细胞增殖和DNA损伤、加速伤口愈合和阻止细胞凋亡来建立有利于癌症发展的环境； (2)重复施用驱虫药吡喹酮来治疗维韦里尼蠕虫(Ov)感染，会导致胆管炎症增加，从而促进肿瘤发生。该研究将通过评估 Ov-ES 的能力来研究这些现象：(1) 促进哺乳动物细胞的伤口修复； (2)促进细胞侵袭和迁移； (3)干扰细胞凋亡。为了进一步研究这些蛋白质的致癌作用，我们将给仓鼠接种 Ov-ES 及其特定成分，以确定这种干预措施是否可以预防肝吸虫感染和 CCA，并评估重复 PZQ 治疗对加速肿瘤发生的影响。