Aflatoxin B1 hepatocarcinogenesis in the mGSTA3-/- mouse

黄曲霉毒素 B1 在 mGSTA3-/- 小鼠中的肝癌发生

• 批准号: 8629710
• 负责人: STEWART SELL
• 金额: $ 28.39万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629710
• 关键词: Acute; Address; Adult; Aflatoxin B1; Aflatoxins; Animals; Antioxidants; Appearance; Breeding; Cancer Etiology; Cell Proliferation; Cells; Chronic Hepatitis; Collaborations; DNA Adduction; Development; Diet; Differentiation and Growth; Dose; Drug Metabolic Detoxication; Ductal; Enzymes; Event; Evolution; Exhibits; Experimental Models; Female; Future; Gene Expression Profile; Gene Mutation; Glutathione S-Transferase; Goals; Growth; Health; Hepatitis; Hepatitis B Virus; Hepatitis B X-Protein; Hepatocarcinogenesis; Hepatocyte; Hepatotoxicity; Histologic; Human; In Vitro; Injury; Knock-out; Knockout Mice; Label; Laboratories; Lead; Lesion; Liver; Liver Stem Cell; Liver neoplasms; Malignant neoplasm of liver; Measures; Metabolism; Modeling; Mus; Nanotechnology; Organism; Outcome; Pathway interactions; Pattern; Pharmacy facility; Play; Population; Predisposition; Prevention; Prevention strategy; Primary carcinoma of the liver cells; Process; Proliferating; Protocols documentation; Rattus; Reactive Oxygen Species; Regimen; Reporting; Resistance; Rest; Risk Factors; Role; Sex Characteristics; Stem cells; Testing; Time; Tissues; Toxic effect; Transgenic Mice; Transplantation; aflatoxin B1-DNA adduct; cancer stem cell; carcinogenesis; carcinogenicity; cell growth; clinically relevant; college; design; in vivo; insight; liver injury; male; mortality; mouse model; nanoparticle; novel; oval cell; oxidative damage; prevent; repaired; research study; response; tissue regeneration; tumor

DESCRIPTION (provided by applicant): We propose to use a new experimental model of aflatoxin hepatocarcinogenesis in glutathione S- transferase A3 knockout mice (mGSTA3-/- or KO) to explore the role of oval cells (OCs) as precursors to hepatocellular carcinoma (HCC) not possible in other experimental models. HCC is a leading cause of cancer mortality worldwide, and dietary aflatoxin B1 (AFB1) exposure is a major risk factor. Adult mice are resistant to AFB1-induced liver injury because of high levels of constitutively expressed mGSTA3 that detoxifies activated AFB1. Humans do not have this efficient detoxification pathway, so that the mGSTA3-/- mice may be considered humanized in regard to AFB1 metabolism and sensitivity. Both male and female mGSTA3 KO mice respond to low doses of AFB1 with liver injury and massive OC proliferation. In Specific Aim 1, we will define the effects of loss of the mGSTA3 on AFB1-induced toxicity, by measuring the steps of AFB1 metabolism, the levels of AFB1-DNA adducts and extent of oxidative damage in liver tissues. This will provide a mechanistic insight into AFB1 carcinogenesis and should explain the differences in susceptibility to acute AFB1 toxicity between male and female mGSTA3-/- mice that we have observed. In Specific Aim 2, four regimens of AFB1 exposure in mGSTA3-/- mice will be used to determine one, or several, that would best serve to study the AFB1-induced injury and development of HCCs. The models will be designed to target oval cells, mimic initiation + promotion protocols and include cross-breeding with chronic hepatitis-prone transgenic mice. In Specific Aim 3, the fate of oval cells after proliferation will be specifically addressed. Following AFB1- induced liver injury, their origin, expansion and differentiation into either mature cells or to liver cancer, will be studied under different AFB1 exposure protocols. The oval cell response in mGSTA3-/- mice is much greater, different in growth pattern and more relevant to human health than other mouse models reported. These studies will provide new insights into aflatoxin B1-associated carcinogenesis, identify the sequence of events that leads to tumor development, determine the role of oval cells as cancer stem cells and provide mechanisms that can be targeted to prevent AFB1-induced liver toxicity and cancer in the future.

描述（由申请人提供）：我们建议使用谷物毒素肝癌的新实验模型在谷胱甘肽S-转移酶A3敲除小鼠（MGSTA3 - / - 或KO）中探索椭圆形细胞（OCS）作为肝细胞电脑营养瘤（HCC）的前体的作用。 HCC是全球癌症死亡率的主要原因，饮食中黄曲霉毒素B1（AFB1）暴露是主要危险因素。成年小鼠对AFB1诱导的肝损伤具有抗药性，这是由于高水平的组成型MGSTA3，可解毒激活的AFB1。人类没有这种有效的排毒途径，因此MGSTA3 - / - 小鼠可以将人为人性化，以实现AFB1代谢和敏感性。雄性和雌性MGSTA3 KO小鼠对低剂量的AFB1均因肝损伤和大量OC的反应反应。在特定目标1中，我们将通过测量AFB1代谢的步骤，AFB1-DNA加合物的水平以及肝组织中氧化损伤的程度来定义MGSTA3损失对AFB1诱导的毒性的影响。这将提供对AFB1致癌作用的机理见解，并应解释我们观察到的雄性和雌性MGSTA3 - / - 小鼠之间急性AFB1毒性的敏感性差异。在特定的目标2中，将使用MGSTA3 - / - 小鼠中AFB1暴露的四个方案来确定一种或几种最能用于研究AFB1诱导的HCC的损伤和发育。这些模型将设计用于靶向椭圆形细胞，模仿起始 +促进方案，并包括与慢性肝炎的转基因小鼠交叉繁殖。在特定的目标3中，将特别解决增殖后椭圆形细胞的命运。在AFB1诱导的肝损伤之后，将根据不同的AFB1暴露方案研究其起源，扩张和分化为成熟细胞或肝癌的分化。 MGSTA3 - / - 小鼠中的椭圆形细胞反应比其他小鼠模型所报告的更大，在生长模式上不同，并且与人类健康更相关。这些研究将提供对黄曲霉毒素B1相关的致癌作用的新见解，确定导致肿瘤发育的事件的序列，确定椭圆形细胞作为癌症干细胞的作用，并提供旨在防止AFB1诱导的肝脏毒性和癌症的机制。