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.

这项研究涉及胆管癌(CCA)，胆道癌，由肝吸虫感染引起， 奥维里尼刺蜂CCA是一种起源于胆汁上皮(胆管细胞)的原发癌症。 风管。它潜伏期长，是侵袭性的，转移，预后很差。它们的作用机制 慢性吸虫感染导致CCA的结果可能是多因素的，但其中一个机制是分泌 具有有丝分裂和抗凋亡特性的寄生虫蛋白，这两种特性都是癌前细胞的特征 环境。我们已经确定了O.viverrini的排泄/分泌产物的特征，并鉴定了两种 对这些过程至关重要的候选ES蛋白-我们证明了人类的一个同源物 分泌型生长因子颗粒与胆管细胞结合并刺激成纤维细胞和CCA的增殖 细胞系。我们还发现，分泌的硫氧还蛋白过氧化物酶可以阻断受损的细胞的凋亡。 胆管细胞。慢性胸椎病进展为CCA遵循多因素途径(S)。我们 假设沿途的关键过程包括(1)寄生虫蛋白的分泌，这些蛋白可以诱导 通过促进胆道病理改变和建立有利于癌症发展的环境 细胞增殖和DNA损伤，加速伤口愈合，阻断细胞凋亡；和(2)反复 使用驱虫药吡喹酮治疗生根性血吸虫感染，可引起 胆管炎症增加，从而加速肿瘤的形成。这项研究将对 这些现象通过评估卵子-ES的能力来实现：(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。为了进一步解决癌症的致癌作用， 这些蛋白质，我们将用Ov-ES及其定义的成分接种仓鼠，以确定这是否 干预对肝吸虫感染和CCA的保护作用及重复PZQ的影响评估 加速肿瘤发生的治疗。 相关性(请参阅说明)： 尽管开展了治疗和健康教育活动，但新城疫原虫的感染率仍然很高。 泰国东北部；更严重的问题是，感染活体奥氏菌通常会导致一种致命的肝脏 癌症。这里提出的工作在分子水平上研究了肝吸虫感染是如何导致这种情况的。 肝癌，并可能提供新的策略来控制这种疾病。