A novel mouse prostate carcinogenesis model for dietary cancer prevention researc

描述（由申请方提供）：本项目的目的是使用hCYP 1A小鼠和PhIP开发一种新型前列腺癌模型，以表征致癌作用的分子变化，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，-TmT是一种更有效的化学预防剂。假设是：1）PhIP通过引起伴随氧化应激和炎症的致突变DNA加合物形成来诱导前列腺癌发生，2）高脂饮食（HFD）可以促进癌发生，缩短实验周期;和3）-TmT可以由于其抗氧化和抗炎作用以及其对致癌信号通路的抑制而抑制前列腺癌发生。具体目标如下：目标1。在hCYP 1A小鼠中建立PhIP诱导的前列腺癌模型，并表征相关的细胞/分子变化。将PhIP（200 mg/kg，po）给予维持AIN 76 A饲料的雄性hCYP 1A小鼠;然后将其保持AIN 76 A饲料或HFD（含20%脂肪）。将在第20、30、40和50周监测前列腺病变和癌症的发展。我们将分析PIN和前列腺癌的发展，并确定细胞增殖水平（Ki 67和PCNA），凋亡（裂解的caspase-3和TUNEL），炎症（NF-kB和CD 45）和氧化应激免疫组化检测GST P1、E-cadherin、考克斯-2、p63、p27、Pten、Nkx3.1、p16、Bcl-2的表达。在开发更快的模型时，我们还可以检验HFD促进前列腺癌发生的假设。还将探讨饮食中添加PhIP对前列腺癌的诱导作用。目标二。测定生育酚对前列腺癌的预防作用。将PhIP处理的hCYP 1A小鼠置于HFD或补充有-TmT的HFD上。-TmT预期降低前列腺中的氧化和亚硝化应激和炎症以及致癌信号传导，并预防或延迟PIN病变和前列腺癌的发作。影响：这项研究将通过以下方式对前列腺癌研究产生影响：1）开发一种新的相关模型来研究饮食因素和前列腺癌; 2）评估高脂肪饮食作为风险因素; 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.