RETINOID RECEPTOR FUNCTION IN SKIN CANCER PROGRESSION
RETINOID RECEPTOR FUNCTION IN SKIN CANCER PROGRESSION
批准号:
6376867
负责人:
JOHN L CLIFFORD
金额:
$10.57万
依托单位国家:
美国
项目类别:
财政年份:
1998
资助国家:
美国
项目状态:
已结题
起止时间:
1998-07-01 至 2003-06-03
中文摘要
鳞状细胞癌(SCC)是临床上最具侵袭性的形式,
非黑色素瘤皮肤癌,尽管积极治疗,
浸润性SCC病变复发率很高(30%)。 因而
迫切需要开发改进的治疗和
预防性治疗这种疾病。 维甲酸很重要
上皮分化和增殖的调节剂。 类视黄醇
有效治疗和预防上皮癌,
包括皮肤SCC。 然而,这种效应的机制不是
很好理解。 为了更好地设计化学预防疗法
对于皮肤SCC,更多关于维甲酸机制的信息
需要在这个系统中采取行动。 类维生素A发挥作用
主要通过核受体,视黄酸受体(RAR α,
β和γ)和类维生素A X受体(RXR α、β和γ),
类固醇激素受体超家族的成员。 类视黄醇受体
在几个系统中,损失与恶性肿瘤相关,
最近的研究表明,抑制RAR α,RAR γ和
患者SCC中RXR α的表达。 本研究基于
假设类维生素A受体丢失有助于恶性肿瘤的发生,
表型通过使上皮细胞对类维生素A具有抗性,
通常抑制致癌作用。 为了验证这一假设,HaCaT
细胞,一种自发永生化的,非肿瘤性的角质形成细胞,
选择衍生的细胞系。 这些细胞表达两种主要的
通常在皮肤中发现的类维生素A受体,RAR γ和RXR α,以及
保持相同的分化特征和反应,
类维生素A作为正常角质形成细胞。 HaCaT细胞是一种
对于癌前细胞,将用于完成以下任务
具体目标:1.)要创建RAR gamma null、RXT alpha null和
同源重组介导的RAR γ/RXR α双无效细胞
基因靶向2.)为了确定受体表达的缺失
导致改变的细胞表型,特别是关于
致瘤潜力、分化能力和对
维甲酸(RA)水平的变化。3.)第三章重新表达思念
受体(RAR γ或RXR α)在敲除细胞系中的稳定表达
转染以确定推定的表型是否
这是遗传病的直接结果。 体细胞
基因打靶方法已经成功地通过原理
研究人员分析F9胚胎中类维生素A受体功能
癌细胞 预期受体无效的产生
HaCaT细胞将提供一个同样强大的工具来了解
类维生素A受体在皮肤SCC发展中的作用,以及
在表皮分化中的作用。
英文摘要
Squamous cell carcinoma (SCC) is the most clinically aggressive form of
non-melanoma skin cancer and in spite of aggressive treatment, deeply
invasive SCC lesions recur at a high rate (30 percent). Therefore there
is an urgent need for the development of improved therapeutic and
preventive treatments for this disease. Retinoids are important
modulators of epithelial differentiation and proliferation. Retinoids
are effective in the treatment and prevention of epithelial cancers,
including cutaneous SCC. However the mechanism for this effect is not
well understood. In order to better design chemopreventive therapies
for cutaneous SCC, more information about the mechanism of retinoid
action in this system is needed. Retinoids exert their effects
primarily through nuclear receptors, retinoic acid receptors (RARalpha,
beta and gamma) and retinoid X receptors (RXRalpha, beta and gamma),
members of the steroid hormone receptor superfamily. Retinoid receptor
loss has been correlated with malignancy in several systems, and one
recent study has demonstrated a suppression of RARalpha, RARgamma and
RXRalpha expression in SCCs of patients. This study is based on the
hypothesis that retinoid receptor loss contributes to the malignant
phenotype by rendering epithelial cells resistant to retinoids, which
wold normally suppress carcinogenesis. To test this hypothesis, HaCaT
cells, a spontaneously immortalized, nontumorigenic, keratinocyte-
derived cell line was chose. These cells express the two predominant
retinoid receptors normally found in skin, RARgamma and RXRalpha, and
retain the same differentiation characteristics and response to
retinoids as normal keratinocytes. The HaCaT cells, which are a model
for premalignant cells, will be used to accomplish the following
specific aims: 1.) To create RARgamma null, RXTalpha null and
RARgamma/RXRalpha double null cells by homologous recombination-mediated
gene targeting. 2.) To determine whether loss of receptor expression
results in an altered cell phenotype, specifically with regard to
tumorigenic potential, differentiation capacity and response to
alterations in retinoic acid (RA) levels. 3.) To reexpress the missing
receptor (RARgamma or RXRalpha) in the knockout cell lines by stable
transfection in order to determine whether the putative phenotype
observed is the direct result of the genetic lesion. A somatic cell
gene targeting approach has been successfully by the principle
investigator to analyze retinoid receptor function in F9 embryonal
carcinoma cells. It is expected that the generation of receptor null
HaCaT cells will provide an equally powerful tool for understanding the
role of retinoid receptors in the development of cutaneous SCC, as well
as their role in epidermal differentiation.
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批准号:6802658
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批准号:6173954
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负责人:JOHN L CLIFFORD
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批准号:2467547
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项目类别:
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资助金额:$0.06万
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财政年份:1995
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负责人:JOHN L CLIFFORD
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依托单位:
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批准号:2170352
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项目类别:
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资助金额:$0.3万
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依托单位:
海外基金