Opisthorchis Viverrini ES Proteins and the Tumorgenic Environment

Opisthorchis Viverrini ES 蛋白和致瘤环境

• 批准号: 8495207
• 负责人: Thewarach Laha
• 金额: $ 11.24万
• 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/8495207
• 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; Vaccines; 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

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），即胆管癌，由肝吸虫感染引起。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，侵袭性强，易转移，预后差。慢性感染吸虫导致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。我们鉴定了O. viverrini的排泄/分泌（ES）产物，并确定了两个候选ES蛋白，它们是这些过程的核心——我们发现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可阻断受损胆管细胞的凋亡。慢性蛇胸腺病向CCA的进展遵循多因素途径。我们推测这条通路的关键过程包括：(1)寄生虫蛋白的分泌诱导胆道病理，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，建立有利于癌症发展的环境；(2)反复使用驱虫药吡喹酮治疗弧菌感染，导致胆管炎症加剧，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的致癌作用，我们将给仓鼠接种Ov-ES及其定义的成分，以确定这种干预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。