Opisthorchis Viverrini ES Proteins and the Tumorgenic Environment

Opisthorchis Viverrini ES 蛋白和致瘤环境

• 批准号: 8304520
• 负责人: Thewarach Laha
• 金额: $ 10.07万
• 依托单位: KHON KAEN UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8304520
• 关键词: Address; Adolescent; Adult; Age; Apoptosis; Apoptotic; Area; Australia; Bile Duct Epithelium; Bile duct carcinoma; Biliary; Binding; Biological Products; Cambodia; Cancer Etiology; Cancerous; Carcinogens; Cell Line; Cell Proliferation; Cells; Cessation of life; China; Cholangiocarcinoma; Cholecystitis; Cholelithiasis; Chronic; Clonorchis sinensis; Country; Cutaneous; DNA Damage; Development; Diet; Disease; Duodenum; Eastern Europe; Ecology; Environment; Epidemiology; Epithelium; Etiology; Exhibits; Far East; Fasciola hepatica; Fibroblasts; Fibrosis; Fishes; Fresh Water; Growth Factor; Hamsters; Health education; Hepatobiliary; Hepatomegaly; Homologous Gene; Human; In Vitro; Incidence; Infection; Inflammation; Instruction; Intervention; Korea; Laos; Link; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Mammalian Cell; Mitosis; Modeling; Molecular; Mus; Neoplasm Metastasis; New York; Northern Europe; Obstructive Jaundice; Opisthorchiasis; Opisthorchis; Opisthorchis viverrini; Parasites; Pathogenesis; Pathology; Pharmaceutical Preparations; Philippines; Physiological; Praziquantel; Prevalence; Primary carcinoma of the liver cells; Principal Investigator; Process; Proliferating; Property; Proteins; Public Health; Punch Biopsy; Recombinants; Reporting; Research; Role; Route; Secretory Component; Skin; Snails; Staging; Stream; Thailand; Time; Trematoda; Vaccinated; Vaccines; Vietnam; Woman; Work; Wound Healing; bile duct; biliary tract; carcinogenesis; carcinogenicity; cholangiocyte; disorder control; egg; foodborne; granulin; health organization; in vivo; men; migration; outcome forecast; parasitism; pathogen; secretory protein; thioredoxin peroxidase; tumor; tumorigenesis; tumorigenic

The research deals with cholangiocarcinoma (CCA), bile duct cancer, caused by infection with the liver fluke, Opisthorchis viverrini. CCA is a primary cancer originafing 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 mulfi-factorial, but one mechanism is the secrefion 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) secrefion 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 administrafion of the anthelminfic drug praziquantel, for treatment of O. viverrini (Ov) infection, causes increased inflammation in the bile ducts and thereby precipitates tumorigenesis. The research will invesfigate 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 intervenfion can protect against liver fluke infecfion and CCA, and assessment of impact of repeated PZQ therapy in accelerafing tumorigenesis. RELEVANCE (See instructions): Despite treatment and health education campaigns, the prevalence of O. viverrini infection remains high in Northeast Thailand; more problemafically, infecfion with O. viverrini often leads to a deadly form of liver cancer. The work proposed here invesfigates - at the molecular level - how liver fluke infection causes this liver cancer, and could offer new strategies to control this disease.

该研究涉及胆管癌（CCA），胆管癌，是由肝fl幸的感染引起的 Opisthorchis viverrini。 CCA是胆汁上皮（胆管细胞）中的原发性癌症 管道。它具有长期的潜伏期，具有侵入性，转移且预后令人沮丧。所在的机制 CCA的慢性感染可能是Mulfi的基础，但一种机制是Secrefion 具有有丝分裂和抗凋亡特性的寄生虫蛋白的蛋白质，这是癌前细胞的特征 环境。我们已经表征了O. viverrini的排泄/分泌物（ES）产品，并确定了两个 这些过程中核心的候选ES蛋白质 - 我们证明了人类的同源物 分泌的生长因子颗粒蛋白与胆管细胞结合并刺激成纤维细胞和CCA的增殖 细胞系。我们还表明，分泌的硫氧还蛋白过氧化物酶阻断受损的凋亡 胆管细胞。慢性粘菌病到CCA的进展遵循了多因素途径。我们 假设沿路线的关键过程包括（1）诱导的寄生虫蛋白的隔离 胆道中的病理学，并通过促进有利于癌症发展的环境 细胞增殖和DNA损伤，加速伤口愈合并阻塞凋亡； （2）重复 用于治疗O. viverrini（OV）感染的Anthminfif药物的行政管理 胆管的炎症增加，从而导致肿瘤发生。这项研究将使 通过评估OV-E（1）促进哺乳动物细胞伤口修复的能力来评估这些现象； （2） 促进细胞入侵和迁移； （3）干扰凋亡。进一步解决 这些蛋白质，我们将用OV-E及其定义的成分接种仓鼠，以确定是否 干预可以预防肝fluke fluke Incfion和CCA，并评估重复PZQ的影响 在加速肿瘤发生中的治疗。 相关性（请参阅说明）： 尽管进行了治疗和健康教育运动，但O. viverrini感染的患病率仍然很高 泰国东北；更有问题的是，viverrini的无效通常会导致肝脏的致命形式 癌症。这里提出的作品在分子水平上提出的作品 - 肝炎感染如何导致此 肝癌，可以提供控制这种疾病的新策略。