Role of AhR/Arnt Signaling Pathway in Carcinogenesis

AhR/Arnt 信号通路在癌变中的作用

• 批准号: 7031775
• 负责人: LORI A WHITE
• 金额: $ 21.39万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7031775
• 关键词: aromatic hydrocarbon receptor; biological signal transduction; carcinogenesis; cell cell interaction; cell line; cell migration; dioxins; melanoma; metalloendopeptidases; molecular pathology; neoplasm /cancer invasiveness; neoplastic process; plasminogen activator inhibitors; protein structure function; radiation carcinogenesis; receptor expression

DESCRIPTION (provided by applicant): Malignant melanoma is on the rise in industrialized nations. Indeed, the incidence of mortality related to melanoma has increased by 34% in the United States from 1973-1992. However, there are few effective treatments developed for melanoma. We propose that the aryl hydrocarbon receptor (AhR) pathway plays a role in melanoma progression through the activation of matrix remodeling enzymes. We have chosen to use 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as the agent to activate the AhR- pathway. TCDD and related polycyclic and halogenated aromatic hydrocarbons (PAH/HAH) are ubiquitous environmental contaminants that are the unintentional by-products of industrial combustion. TCDD is ideal for examination of the AhR pathway in melanoma for three reasons: (1.) skin is a target tissue for TCDD-activation of the AhR pathway; (2.) and TCDD is not metabolized; and (3) TCDD is non-mutagenic, and therefore the effects we observe should be directly related to activation of the AhR pathway. We hypothesize that TCDD-activation of the AhR/Arnt pathway stimulates melanoma progression by altering expression of the genes involved in matrix remodeling, specifically the matrix metalloproteinases (MMPs). MMP activity is necessary for cell migration through matrix barriers, and expression of these enzymes correlates with aggressive and invasive tumors. Our preliminary data in melanoma cells demonstrate that both non-invasive and invasive melanoma lines are responsive to TCDD, and invasive melanoma cells express MMPs in response to TCDD exposure. Further, we also show increased invasiveness of melanoma cells when treated with TCDD. This suggests that TCDD directly increases melanoma invasion by activating matrix degradation. Therefore, the specific aims for this proposal are: (1.) Elucidate the molecular mechanism mediating TCDD-induced expression of MMPs in melanoma cell lines. (2.) Elucidate the role of the AhR in TCDD-induced changes in MMP expression in melanoma. (3.) Demonstrate the role of the AhR pathway in melanoma migration and invasion using an in vitro invasion assay. (4.) Using a three-dimensional skin model system, determine the role of cell-cell interaction on AhR-activation of MMP expression.

描述（由申请人提供）：恶性黑色素瘤在工业化国家呈上升趋势。事实上，从1973-1992年，美国与黑色素瘤相关的死亡率增加了34%。然而，很少有针对黑色素瘤的有效治疗方法。我们提出，芳烃受体（AhR）途径发挥了作用，通过激活基质重塑酶在黑色素瘤的进展。我们选择使用2，3，7，8-四氯二苯并-p-二恶英（TCDD）作为激活AhR-途径的试剂。四氯二苯并对二恶英及其相关的多环芳烃和卤代芳烃（PAH/HAH）是工业燃烧过程中产生的一种环境污染物。TCDD是检查黑色素瘤AhR通路的理想方法，原因有三：（1）皮肤是AhR通路TCDC激活的靶组织;（2.）TCDD不被代谢;（3）TCDD无致突变性，因此我们观察到的效应应与AhR通路的激活直接相关。我们假设TCDD激活AhR/Arnt通路通过改变参与基质重塑的基因，特别是基质金属蛋白酶（MMPs）的表达来刺激黑色素瘤进展。MMP活性是细胞迁移通过基质屏障所必需的，并且这些酶的表达与侵袭性和侵袭性肿瘤相关。我们在黑色素瘤细胞中的初步数据表明，非侵袭性和侵袭性黑色素瘤细胞系均对TCDD有反应，侵袭性黑色素瘤细胞表达MMP以响应TCDD暴露。此外，我们还显示了增加的黑色素瘤细胞的侵袭性时，用TCDD治疗。这表明TCDD通过激活基质降解直接增加黑色素瘤侵袭。因此，本提案的具体目标是：（1）阐明TCDD诱导黑色素瘤细胞表达MMPs的分子机制。（2.）阐明AhR在TCDD诱导的黑素瘤MMP表达变化中的作用。（3.）使用体外侵袭试验证明AhR途径在黑色素瘤迁移和侵袭中的作用。（4.）使用三维皮肤模型系统，确定细胞-细胞相互作用对MMP表达的AhR活化的作用。