A novel mouse prostate carcinogenesis model for dietary cancer prevention researc

用于饮食癌症预防研究的新型小鼠前列腺癌模型

• 批准号: 8450080
• 负责人: CHUNG S. YANG
• 金额: $ 7.29万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450080
• 关键词: 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Atrophic; BCL2 gene; Cancer Etiology; Carcinogens; Carcinoma; Cell Proliferation; Cessation of life; Chemopreventive Agent; Cleaved cell; Colon; Cytochrome P450; DNA Adduction; Development; Diet; Dietary Factors; Drug Metabolic Detoxication; E-Cadherin; Epidemiologic Studies; Epigallocatechin Gallate; Epithelial Cells; Epithelium; Etiology; Fatty acid glycerol esters; Fishes; GSTP1 gene; Heterocyclic Amines; Human; Immunohistochemistry; In Situ Nick-End Labeling; Incidence; Inflammation; Inflammatory; Inherited; Intake; Lesion; Lymphoid Tissue; Malignant Neoplasms; Malignant neoplasm of prostate; Mammary gland; Meat; Medical; Modeling; Molecular; Monitor; Mus; NF-kappa B; Oncogenic; Oxidative Stress; PTGS2 gene; PTPRC gene; Pathogenesis; Pathway interactions; Phytoestrogens; Preventive; Process; Prostate; Prostate carcinoma; Prostatic Intraepithelial Neoplasias; Public Health; Rattus; Reporting; Research; Risk; Risk Factors; Selenium; Signal Pathway; Signal Transduction; Study models; Testing; Tocopherols; United States; Vitamin D; Wild Type Mouse; anticancer research; cancer prevention; cancer risk; carcinogenesis; caspase-3; cell injury; cooking; dietary supplements; environmental mutagens; foodborne; fruits and vegetables; insight; male; men; nitrosative stress; novel; prevent; prostate cancer model; prostate cancer prevention; prostate carcinogenesis; tumor

DESCRIPTION (provided by applicant): The objectives of this project are to develop a novel prostate cancer model using hCYP1A mice and PhIP, to characterize the molecular changes of carcinogenesis, and to determine the prostate cancer preventive activity of a -tocopherol (-T) rich mixture of tocopherols (-TmT) which, unlike -T, is a more effective chemopreventive agent. The hypotheses are: 1) PhIP induces prostate carcinogenesis by causing mutagenic DNA-adduct formation accompanied by oxidative stress and inflammation, 2) a high-fat diet (HFD) can promote carcinogenesis, shortening the experimental period; and 3) -TmT can inhibit prostate carcinogenesis due to its antioxidant and anti-inflammatory actions as well as its inhibition of oncogenic signaling pathways. The specific aims are as follows: Aim 1. Develop the PhIP-induced prostate cancer model in hCYP1A mice and characterize the cellular/molecular changes involved. PhIP will be administered (200mg/kg, po) to male hCYP1A mice maintained on the AIN76A diet; then they will be kept either on AIN76A diet or the HFD (containing 20% fat). The development of prostate lesions and cancer will be monitored at 20, 30, 40, and 50 weeks. We will analyze the development of PIN and carcinoma in the prostate as well as determine the levels of cell proliferation (Ki67 and PCNA), apoptosis (cleaved caspase-3 and TUNEL), inflammation (NF-kB and CD45), and oxidative stress (8-OHdG and -H2AX), as well as the expression of GSTP1, E-cadherin, COX-2, p63, p27, Pten, Nkx3.1, p16, and Bcl-2 by immunohistochemistry (IHC). In the development of a faster model, we can also test the hypothesis that HFD promotes prostate carcinogenesis. The induction of prostate cancer by PhIP added to the diet will also be explored. Aim 2. Determine the prostate cancer preventive activity of tocopherols. The PhIP-treated hCYP1A mice will be put on the HFD or HFD supplemented with -TmT. -TmT is expected to decrease oxidative and nitrosative stress and inflammation as well as oncogenic signaling in the prostate, and prevents or delays the onset of PIN lesions and prostate carcinoma. Impact: This research will make an impact in prostate cancer research by 1) developing a novel and relevant model to study dietary factors and prostate cancer; 2) evaluating high fat diet as a risk factor; and 3) determining -TmT as a chemopreventive agent for prostate cancer.

描述（由申请人提供）：该项目的目标是使用 hCYP1A 小鼠和 PhIP 开发一种新型前列腺癌模型，以表征癌发生的分子变化，并确定富含α-生育酚 (-T) 的生育酚混合物 (-TmT) 的前列腺癌预防活性，与 -T 不同，它是一种更有效的化学预防剂。假设是：1）PhIP通过引起诱变DNA加合物形成并伴有氧化应激和炎症来诱导前列腺癌发生；2）高脂饮食（HFD）可以促进癌变，缩短实验周期； 3) -TmT 由于其抗氧化和抗炎作用以及对致癌信号通路的抑制作用，可以抑制前列腺癌的发生。具体目标如下： 目的 1. 在 hCYP1A 小鼠中开发 PhIP 诱导的前列腺癌模型并表征所涉及的细胞/分子变化。将 PhIP（200mg/kg，口服）给予维持 AIN76A 饮食的雄性 hCYP1A 小鼠；然后他们将继续采用 AIN76A 饮食或 HFD（含 20% 脂肪）。将在第 20、30、40 和 50 周时监测前列腺病变和癌症的发展。我们将分析前列腺中 PIN 和癌的发展，并确定细胞增殖（Ki67 和 PCNA）、细胞凋亡（裂解的 caspase-3 和 TUNEL）、炎症（NF-kB 和 CD45）和氧化应激（8-OHdG 和 -H2AX）的水平，以及 GSTP1、E-cadherin、COX-2、p63、 通过免疫组织化学 (IHC) 检测 p27、Pten、Nkx3.1、p16 和 Bcl-2。在开发更快的模型时，我们还可以检验 HFD 促进前列腺癌的假设。还将探讨通过添加到饮食中的 PhIP 诱导前列腺癌。目标 2. 确定生育酚的前列腺癌预防活性。 PhIP处理的hCYP1A小鼠将被置于HFD或补充有-TmT的HFD上。 -TmT 有望减少氧化和亚硝化应激以及炎症以及前列腺中的致癌信号传导，并预防或延迟 PIN 病变和前列腺癌的发生。影响：这项研究将对前列腺癌研究产生影响：1）开发一种新颖且相关的模型来研究饮食因素和前列腺癌； 2）将高脂肪饮食评估为危险因素； 3)确定-TmT作为前列腺癌的化学预防剂。