Etiology and Prevention of Oral Cancer

描述(由申请人提供)：描述了一种人类头颈部鳞状细胞癌(HNSCC)进展的模型，其中包括细胞周期蛋白D1的上调，Stat-3的激活，以及高水平的环氧合酶-2(COX-2)的表达。还观察到P53和其他抑癌基因(如Rb、p16)的突变和失活。初级预防，例如停止吸烟、减少饮酒和增加水果和蔬菜的摄入量，似乎对相当一部分人口来说是无法实现的。因此，正在探索其他方法，如化学预防。我们报道了1，4-亚苯基双(亚甲基)硒氰酸酯(p-XSC)对4-硝基喹啉-N-氧化物(NQO)处理的大鼠舌癌的抑制作用。P-XSC还能抑制培养的人口腔癌细胞的生长和/或诱导细胞凋亡，抑制小鼠舌中苯并[a]芘(B[a]P)-DNA加合物的形成，从而具有抑制苯并[a]P诱导的舌肿瘤形成的潜力。基于前人的研究，我们推测p-XSC通过多种机制抑制肿瘤的发生，包括抑制DNA损伤和细胞增殖，以及诱导癌前和转化细胞的凋亡。为了验证我们的假设，我们提出了以下具体目标：目的1：阐明p-XSC抑制NQO诱导的舌癌发生的机制。在肿瘤诱导过程中，我们将确定-XSC在以下方面的作用：a)NQO诱导的DNA损伤；b)NQO在体内(在LACI大鼠中)诱导的突变；c)NQO诱导的(I)细胞增殖、(Ii)细胞凋亡以及(Iii)与HNSCC发展有关的细胞周期、细胞增殖和细胞凋亡的蛋白质(cyclin d1、Stat-3、COX-2、p16、pRB和P53)。还将使用EDNA微阵列分析来检测全球基因表达的变化；目标2：确定p-XSC对苯并[a]P诱发小鼠舌癌和目标1中所述终点的影响；以及目标3：利用正常细胞、白斑和鳞状细胞癌的培养，确定NQO或B[a]P和p-XSC单独和联合对目标1中所述的某些生化、分子和细胞事件的影响。据我们所知，这项应用是第一次确定烟草烟雾致癌物(B[a]P)是否会改变那些已知与HNSCC有关的基因，从而为口腔癌的病因学提供重要线索。该项目的长期应用可能会导致HNSCC的预防和控制策略。通过确定舌癌发生的关键干预靶点，应该有可能最大限度地减少基础研究和临床应用之间的差距，并导致转化性的临床干预。

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.