RETINOID EFFECTS ON SQUAMOUS CELL CARCONOMAS

视黄醇对鳞状细胞癌的作用

• 批准号: 2131315
• 负责人: LORRAINE J GUDAS
• 金额: $ 21.67万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-06-01 至 1997-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2131315
• 关键词: cell growth regulation; clone cells; epithelium; fibrous protein; gene expression; genetic markers; genetic promoter element; genetic regulation; genetic strain; gingiva; human tissue; keratin; laboratory mouse; messenger RNA; mouth neoplasms; neoplasm /cancer genetics; neoplasm /cancer nutrition therapy; neoplastic transformation; nutrition related tag; oral mucosa; palate; receptor expression; retinoid binding proteins; retinoids; skin; squamous cell carcinoma; tongue; transfection; vitamin metabolism

Squamous cell carcinomas account for nearly 90% of the cancers in the oral cavity and there is dramatic new clinical evidence that retinoids (vitamin A and its natural and synthetic derivatives, including retinoic acid (RA) can suppress the development of oral squamous cell carcinomas in humans. The mechanism by which retinoids act to inhibit neoplastic transformation is unknown. Therefore, this grant proposes experiments aimed at measuring a number of different effects of retinoids in a variety of cultured normal human epithelia and in several human squamous cell carcinoma (SCC) lines from various regions of the oral cavity and facial epidermis. The normal human epithelial cell strains that will be analyzed include those from the soft palate, floor of mouth, buccal mucosa, ventral tongue, gingiva, hard palate, and facial epidermis. The squamous cell carcinoma (SCC) lines to be analyzed include those from the soft palate, the floor of mouth, the ventral tongue, and the facial epidermis. Preliminary experiments have shown that normal epithelial cell subtypes from different areas of the oral cavity display different degrees of responsiveness to the same concentration of retinoic acid added to the culture medium. A goal of future experiments is to understand the molecular basis for such differences in RA responsiveness. Specifically, we will quantitate the levels of expression of the genes that mediate RA action--the receptors RAR alpha, RAR beta, RAR gamma and RXR alpha; the CRABP and CRABP-II; and the CRBP. Because the intracellular metabolism of retinol and RA may differ in normal epithelial cell subtypes from different locations in the oral cavity, the metabolism of these agents will also be assessed. We have shown that the SCC lines display aberrant responses to RA. Specifically, the keratin K19 gene is aberrantly regulated (i.e., either expressed constitutively or not expressed at all) in the SCC lines; in contrast, in normal epithelial cells K19 expression is regulated by RA. Thus, the K19 gene will be analyzed to ascertain why it is no longer regulated by RA in SCC cells. Furthermore, no RAR beta mRNA expression is detected in the six SCC lines tested to date, even when the SCC lines are derived from a region of the oral cavity such as the soft palate, where normal epithelial cells exhibit high levels of RAR beta mRNA. Therefore, in future studies the RAR beta gene will be examined to determine why it is not expressed in SCC lines, and a functional RAR beta gene in an expression vector will be reintroduced into the SCC cells to determine if overexpression of the RAR beta gene reverses any of the tumorigenic properties of the SCCs. The metabolism of RA in the SCC lines will also be measured, as aberrant catabolism of RA may be related to the observed abnormalities in K19 and RAR beta expression in the SCC cells. These experiments should provide a greater understanding of the actions of RA in epithelial cells. More knowledge of the differences among normal epithelial cell subtypes from different regions of the oral cavity and between normal and malignant transformed epithelia will also be gained. These studies should lead to advances in the clinical treatment of cancerous and precancerous lesions in the oral cavity.

鳞状细胞癌占口服癌症的近90％ 腔体有巨大的新临床证据表明类视网膜类似（维生素 A及其天然和合成衍生物，包括视黄酸（RA） 可以抑制人类口服鳞状细胞癌的发展。 类视视性类动物起作用抑制肿瘤转化的机制 是未知的。 因此，该赠款提出了旨在衡量的实验 类维生素类似于各种培养的正常的多种不同的影响 人类上皮和几种人类鳞状细胞癌（SCC）系 来自口腔和面部表皮的各个区域。 正常 将要分析的人类上皮细胞菌株包括 柔软的口感，嘴地板，颊粘膜，腹舌，金格瓦，硬 口感和面部表皮。 鳞状细胞癌（SCC）线 可以分析包括柔软的口感，嘴地板， 腹舌和面部表皮。 初步实验具有 表明来自口服不同区域的正常上皮细胞亚型 腔显示出不同程度的响应能力 视黄酸的浓度添加到培养基中。 一个目标 未来的实验是了解这样的分子基础 RA响应能力的差异。 具体来说，我们将量化 介导RA作用的基因的表达水平 - 受体RAR Alpha，Rar Beta，Rar Gamma和RXR Alpha； Crabp和Crabp-II；和 CRBP。 因为视黄醇和RA的细胞内代谢可能有所不同 来自口服不同位置的正常上皮细胞亚型 腔体，这些药物的代谢也将得到评估。 我们有 表明SCC线对RA表示异常的响应。 具体来说， 角蛋白K19基因被异常调节（即表达 SCC线中的组成型或根本不表达；相反，在 正常的上皮细胞K19表达受RA调节。 因此，K19 将分析基因以确定为什么不再受到RA的调节 SCC细胞。 此外，在六个 即使从区域得出SCC线，迄今已测试的SCC线也已测试 口腔诸如柔软的口腔，正常上皮细胞 表现出高水平的RAR Beta mRNA。 因此，在以后的研究中 将检查Beta基因以确定为什么在SCC中未表达它 线，表达矢量中的功能性RAR Beta基因将是 重新引入SCC细胞以确定RAR的过表达是否 β基因逆转SCC的任何致瘤特性。 这 SCC线中RA的代谢也将被测量为异常 RA的分解代谢可能与K19中观察到的异常有关 SCC细胞中的RAR Beta表达。 这些实验应提供 对RA在上皮细胞中的作用有更多了解。 更多的 了解正常上皮细胞亚型的差异 口腔的不同区域以及正常和恶性之间 转化的上皮也将获得。 这些研究应导致 在癌症和癌前病变的临床治疗方面的进步 口腔。