Opisthorchis Viverrini ES Proteins and the Tumorgenic Environment

Opisthorchis Viverrini ES 蛋白和致瘤环境

• 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
• 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

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），胆管癌，由肝吸虫感染引起，猫尾后睾吸虫。CCA是一种原发于胆管上皮（胆管细胞）的癌症。它潜伏期长，具有侵袭性，转移性，预后差。吸虫慢性感染导致CCA的机制可能是多因素的，但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，这两种特性都是癌前细胞环境的特征。我们对O. viverrini和确定了两个候选的ES蛋白，这些过程的核心-我们表明，人类分泌的生长因子，颗粒蛋白的同源物，结合到胆管细胞和刺激成纤维细胞和CCA细胞系的增殖。我们还发现，分泌的硫氧还蛋白过氧化物酶阻断受损胆管细胞的凋亡。慢性后睾吸虫病进展为CCA遵循多因素途径。我们推测，这一途径的关键过程沿着包括：（1）分泌寄生虫蛋白，通过促进细胞增殖和DNA损伤，加速伤口愈合和阻断细胞凋亡，诱导胆道病变，建立有利于癌症发展的环境;（2）反复给予驱虫药吡喹酮，治疗O.灵猫（Ov）感染引起胆管中炎症增加，从而促使肿瘤发生。该研究将通过评估Ov-ES（1）促进哺乳动物细胞伤口修复;（2）促进细胞侵袭和迁移;（3）干扰细胞凋亡的能力来研究这些现象。为了进一步解决这些蛋白质的致癌作用，我们将用Ov-ES及其定义的组分接种仓鼠，以确定这种干预是否可以防止肝吸虫感染和CCA，并评估重复PZQ治疗对加速肿瘤发生的影响。