Role of Osteopontin in Tumor Promotion

骨桥蛋白在肿瘤促进中的作用

• 批准号: 6435323
• 负责人: PI-LING CHANG
• 金额: $ 30.55万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-18 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6435323
• 关键词: antisense nucleic acid; autocrine; chemical carcinogenesis; gene induction /repression; genetically modified animals; laboratory mouse; neoplasm /cancer genetics; osteopontin; phorbols; skin neoplasms

DESCRIPTION: (PROVIDED BY APPLICANT) Most initiated cells that contain genetic alterations by carcinogens can remain dormant and will not develop into tumors or progress to malignancies unless further internal or external factors, called tumor promoters, persistently stimulate these cells. Therefore, malignancies commonly develop much later in life. The mechanism of tumor promotion is not well understood. Identification of cellular and molecular participants involved in the promotion stage of carcinogenesis is a subject of importance as such information could provide the key to preventing certain malignancies. Our long-term goal is to understand how matrix proteins stimulated by tumor promoters participate in the process of tumorigenesis. Specifically, we will study the secreted, adhesive protein, osteopontin (OPN). OPN expression is elevated in several types of human cancers and premalignant tumors. Experimental evidences support the role of OPN as a mediator of tumor promotion. Thus, we hypothesize that OPN acts as an autocrine stimulus for tumor promotion of initiated cells. To test this hypothesis, we will use both in vitro and in vivo tumor promotion models. Specifically, we intend to determine the extent to which OPN induction is required for tumor promotion in JB6 cells, model for tumor promotion studies. We have developed unique genetic tools, antisense OPN JB6 clones and sense OPN JB6 clones, to determine OPN's effect on colony formation on soft agar and tumorigenicity in immunodeficient mice. We will evaluate the cellular and molecular mechanism(s) whereby OPN transforms JB6 cells. In addition, the importance of OPN in tumor promotion in vivo will be addressed by the lack of OPN expression and targeted expression of OPN in epidermis. Together, these studies will provide a better understanding of the role of OPN in tumor promotion and may contribute to the design of a mechanism-based strategy for cancer prevention.

描述：（由申请人提供）大多数初始细胞含有遗传 致癌物引起的改变可以保持休眠状态，不会发展成肿瘤 或进展为恶性肿瘤，除非进一步的内部或外部因素，称为 肿瘤促进剂持续刺激这些细胞。因此， 通常在生命后期发展。肿瘤促进的机制不是 很好理解。参与的细胞和分子参与者的鉴定 在致癌作用的促进阶段是一个重要的课题 信息可以提供预防某些恶性肿瘤的关键。我们 长期目标是了解基质蛋白如何被肿瘤刺激， 启动子参与肿瘤发生的过程。具体来说，我们将 研究其分泌的粘附蛋白骨桥蛋白（OPN）。OPN表达 在几种类型的人类癌症和癌前肿瘤中升高。 实验证据支持骨桥蛋白作为肿瘤介质的作用 推广.因此，我们假设OPN作为一种自分泌刺激物， 启动细胞的肿瘤促进。为了验证这一假设，我们将使用 体外和体内肿瘤促进模型。具体来说，我们打算 确定OPN诱导在多大程度上是肿瘤促进所必需的， JB6细胞，用于肿瘤促进研究的模型。我们开发了独特的基因 工具，反义OPN JB6克隆和正义OPN JB6克隆，以确定OPN 免疫缺陷对软琼脂集落形成及致瘤性影响 小鼠我们将评估骨桥蛋白在细胞和分子机制， 转化JB6细胞。此外，OPN在肿瘤促进中的重要性也被证实。 体内将通过缺乏OPN表达和靶向表达 表皮中的OPN。总之，这些研究将提供一个更好的理解 OPN在肿瘤促进中的作用，并可能有助于设计一种 基于机制的癌症预防策略。