A novel mouse prostate carcinogenesis model for dietary cancer prevention researc

描述（由申请人提供）：该项目的目标是利用hCYP1A小鼠和PhIP建立一种新的前列腺癌模型，表征癌变的分子变化，并确定富含-生育酚（-T）的生育酚（-TmT）混合物的前列腺癌预防活性，与-T不同，-TmT是一种更有效的化学预防剂。假设：1)PhIP通过引起致突变性dna加合物形成并伴有氧化应激和炎症诱导前列腺癌变；2)高脂饮食（HFD）可促进前列腺癌变，缩短实验周期；3) -TmT具有抗氧化、抗炎作用，抑制前列腺癌变信号通路，从而抑制前列腺癌变。具体目标如下：目标1。在hCYP1A小鼠中建立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, po）给予饲喂AIN76A的雄性hCYP1A小鼠；然后他们将被保持在AIN76A饮食或HFD（含20%脂肪）。前列腺病变和癌症的发展将在20、30、40和50周时进行监测。我们将通过免疫组化（IHC）分析PIN和前列腺癌的发展，以及细胞增殖（Ki67和PCNA）、细胞凋亡（cleaved 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、p27、Pten、Nkx3.1、p16和Bcl-2的表达。在开发更快的模型的过程中，我们还可以验证HFD促进前列腺癌发生的假设。还将探讨膳食中添加PhIP对前列腺癌的诱导作用。目标2。测定生育酚预防前列腺癌的活性。将phip处理的hCYP1A小鼠置于HFD或添加-TmT的HFD中。-TmT有望减少前列腺的氧化应激和亚硝化应激、炎症以及致癌信号，预防或延缓PIN病变和前列腺癌的发生。影响：本研究将在以下方面对前列腺癌研究产生影响：1)建立一种新的、相关的饮食因素与前列腺癌研究模型；2)评价高脂肪饮食为危险因素；3)确定-TmT作为前列腺癌的化学预防剂。

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.