Etiology and Prevention of Oral Cancer

口腔癌的病因和预防

• 批准号: 6961928
• 负责人: KARAM E EL-BAYOUMY
• 金额: $ 30.41万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6961928
• 关键词: DNA damage; apoptosis; benzopyrenes; biomarker; cancer prevention; carcinogenesis inhibitor; cell cycle; cell line; cell proliferation; chemoprevention; cyanate; disease /disorder etiology; gene expression; human tissue; laboratory mouse; laboratory rat; microarray technology; oral leukoplakia; oral pharyngeal neoplasm; proliferating cell nuclear antigen; quinoline; selenium; squamous cell carcinoma; terminal nick end labeling; tongue

DESCRIPTION (provided by applicant): A model of progression of head and neck sqiamous cell carcinoma (HNSCC) in humans has been described which includes up-regulation of cyclin D1, activation of Stat-3, and expression of high levels of cyclooxygenase-2 (COX-2). Mutations and inactivation of p53 and other tumor suppressor genes (e.g. Rb, p16) have also been observed. Primary prevention, e.g., cessation of tobacco use, moderation of alcohol consumption, and increased intake of fruits and vegetables appears unattainable for a significant fraction of the population. Thus, other approaches such as chemoprevention are being explored. We have reported that selenium, as 1,4-phenylenebis(methylene)selenocyanate (p-XSC), inhibited tongue tumors of rats treated with 4-nitroquinoline-N-oxide (NQO). p-XSC also leads to growth inhibition and/or apoptosis in cultured human oral carcinoma cells, inhibits the formation of benzo[a]pyrene (B[a]P)-DNA adducts in the mouse tongue, and therefore has the potential of inhibiting B[a]P-induced tongue tumorigenesis. Based on these previous studies we hypothesize thatp-XSC inhibits tumorigenesis by multiple mechanisms including inhibition of DNA damage and cell proliferation, as well as induction of apoptosis in premalignant and transformed cells. To test our hypothesis we propose the following specific aims, Aim 1: To elucidate the mechanism of inhibition of NQO-induced tongue tumorigenesis by p-XSC. During tumor induction we will determine the effect of-XSC on: a) NQO-induced DNA damage; b) NQO-induced mutagenesis in vivo (in the lacI rat); c) NQO-induced (i) cell proliferation, (ii) apoptosis and (iii) proteins involved in cell cycle, cell proliferation, and apoptosis that have been implicated in the development of HNSCC (cyclin D1, Stat-3, COX-2, p16, pRb and p53). Changes in global gene expression will also be examined using eDNA microarray analysis; Aim 2: To determine the effect of p-XSC on tongue tumor induction by B[a]P in mice and on endpoints described in Aim 1; and Aim 3: To determine the effect of NQO or B[a]P, and p-XSC individually and in combination on certain of the biochemical, molecular and cellular events described in Aim 1 using cultures of normal cells, leukoplakia, and squamous cell carcinoma. To our knowledge, this application is the first to determine whether a tobacco smoke carcinogen (B[a]P) which induces tongue tumors in the mouse, alters those genes that are known to be involved in HNSCC and thus provides important leads toward the etiology of oral cancer. The long-term applications of this project may lead to strategies for the prevention and control of HNSCC. By identifying critical intervention targets in tongue tumorigenesis, it should be possible to minimize the gap between basic research and clinical application, and lead to translational clinical interventions.

描述（由申请人提供）：已描述了人类头颈鳞状细胞癌（HNSCC）的进展模型，其中包括细胞周期蛋白 D1 的上调、Stat-3 的激活以及高水平环氧合酶-2 的表达(COX-2)。还观察到 p53 和其他肿瘤抑制基因（例如 Rb、p16）的突变和失活。对于很大一部分人口来说，一级预防，例如戒烟、适量饮酒以及增加水果和蔬菜的摄入量似乎是无法实现的。因此，正在探索化学预防等其他方法。我们报道了硒，1,4-亚苯基双（亚甲基）硒氰酸酯（p-XSC），可以抑制用 4-硝基喹啉-N-氧化物（NQO）治疗的大鼠的舌肿瘤。 p-XSC 还会导致培养的人口腔癌细胞的生长抑制和/或凋亡，抑制小鼠舌头中苯并[a]芘 (B[a]P)-DNA 加合物的形成，因此具有抑制B[a]P 诱导的舌肿瘤发生。基于这些先前的研究，我们假设 p-XSC 通过多种机制抑制肿瘤发生，包括抑制 DNA 损伤和细胞增殖，以及诱导癌前细胞和转化细胞的凋亡。为了检验我们的假设，我们提出以下具体目标，目标 1：阐明 p-XSC 抑制 NQO 诱导的舌肿瘤发生的机制。在肿瘤诱导过程中，我们将确定-XSC 对以下方面的影响： a) NQO 诱导的 DNA 损伤； b) NQO 诱导的体内诱变（在 lacI 大鼠中）； c) NQO 诱导的 (i) 细胞增殖、(ii) 细胞凋亡和 (iii) 参与 HNSCC 发展的细胞周期、细胞增殖和细胞凋亡蛋白（细胞周期蛋白 D1、Stat-3、COX-2） 、p16、pRb 和 p53）。还将使用 eDNA 微阵列分析来检查全局基因表达的变化；目标 2：确定 p-XSC 对 B[a]P 在小鼠中诱导舌肿瘤的影响以及对目标 1 中描述的终点的影响；目标 3：使用正常细胞、白斑和鳞状细胞培养物确定 NQO 或 B[a]P 和 p-XSC 单独或组合对目标 1 中描述的某些生化、分子和细胞事件的影响癌。据我们所知，该应用首次确定了诱导小鼠舌肿瘤的烟草烟雾致癌物 (B[a]P) 是否改变了已知与 HNSCC 相关的基因，从而为病因学提供了重要线索。口腔癌。该项目的长期应用可能会产生预防和控制 HNSCC 的策略。通过确定舌肿瘤发生的关键干预靶点，应该可以最大限度地缩小基础研究和临床应用之间的差距，并实现转化性临床干预。