Analysis for machanisms invokved in ultraviolct B-light-induced apoptosis in cpidcrmal cells

紫外B光诱导表皮细胞凋亡的机制分析

基本信息

批准号：
11670856
负责人：
ARAGANE Yoshinori
金额：
$ 2.11万
依托单位：
Kinki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

This research project was primarily designed to analyze mechanisms involved in ultraviolet B light (UV)-induced apoptosis of epidermal cells. The theoretical background was 1)UV is regarded as a potent carcinogen of non- melanomatous skin cancers, including squamous ell carcinoma (SCC), basal cell carcinoma (BCC), 2)UV is well known to effectively induce apoptosis of epidermal cells, such as keratinocytes and melanocytesl. Based on these so far available knowledge about apidermal cell apoptosis, we thought if we can use the knowlede regarding apoptosis to manipulate therapics, such as those against cancers. Therefore, to address this concern, we first focused on artificial induction of apoptosis of melanoma cells. We previously could chow that melanoma cells, in advanced stage, vigorously express CD95 ligand (CD95L/APO-1L/FasL). Since almost all types of cells including immunocompetent cells express CD95 (Maeda et al, Br J Dermatol 1998 ; 139 : 198-206), melanoma may counterattackimmun … More e cells by inducing their apoptosis via CD95/CD95L crosslinking. To employ this knowledge, we first were interested whether we could induce apoptosis of CD95L-expressing melanoma cells when we introduce expression of CD95 on melanoma cells. The answer was 'yes', as published by us that ectopic expression of CD95 on CD95L-expressing melanoma led to vigorous apoptosis of those cells. This implies future therapeutic uefulness of this strategy in melanoma thereapy.Although the above study clearly indicates the possible effectiveness of CD95 introduction of CD95L+melanoma cells, we should know when melanoma CD95L is turned on. Therefore, we next analysed using patients' specimens for expression of CD95L consequently, it was found that a melanoma cell, when reaches deeper than 3.5-mm from the outside (corresponding approximately middle dermis), becomes able to express CD95L (Maeda et al, J Dermatol 2001 ; 28 : 499-504). Together, we were able to identify the future feasible strategy to treat melanoma patients by ectopic expression of CD95.Besides melanoma, basal cell carcinoma (BCC) is one of the most frequently encountered dermatological neoplasms worldwide. Since pathegenesis of BCC is not completely clear yet, we next focused about this issue. Therefore, we focused β-catenin, a signaling element of Wnt-signaling pathway and reported to be involved in pathogenesis of colon cancers. To address this issue, we immunostained BCC specimens, revealing that nuclear translocation of β-catenin was observed in approximately 70% of BCC tested, while non of other dermatoses, such as atopic dermatitis, psoriasis, squamous cell carcinoma, gave rise to positive signal in muclei. Because nuclear translocation of this protein is a requisite condition to be involved in carcinogenesis, we concluded that b-catenin is involved in pathogenesis of BCC. Further analysis is required to identify which elements are causal to nuclear translocation of β-catenin. Less

该研究项目主要旨在分析紫外线 B 光 (UV) 诱导表皮细胞凋亡的机制。理论背景是 1) 紫外线被认为是非黑色素瘤皮肤癌的强效致癌物，包括鳞状细胞癌 (SCC)。）），基底细胞癌（BCC），2）众所周知，紫外线可以有效诱导表皮细胞（例如角质形成细胞和黑素细胞）的凋亡。表皮细胞凋亡，我们认为是否可以利用有关细胞凋亡的知识来操纵治疗方法，例如针对癌症的治疗方法，因此，为了解决这个问题，我们首先关注人工诱导黑色素瘤细胞的凋亡。，在晚期阶段，由于几乎所有类型的细胞（包括免疫活性细胞）都表达 CD95，因此大力表达 CD95 配体（CD95L/APO-1L/FasL）（Maeda 等人，Br J）。 Dermatol 1998；139：198-206)，黑色素瘤可能通过 CD95/CD95L 交联诱导细胞凋亡来反击免疫细胞。 CD95 在黑色素瘤细胞上的表达答案是“是”，正如我们所发表的，CD95 在黑色素瘤细胞上的异位表达。表达CD95L的黑色素瘤导致这些细胞的剧烈凋亡，这意味着该策略在黑色素瘤治疗中的未来治疗价值。虽然上述研究清楚地表明CD95引入CD95L+黑色素瘤细胞的可能有效性，但我们应该知道黑色素瘤CD95L何时转变。因此，我们接下来用患者的标本进行CD95L表达分析，结果发现黑色素瘤细胞，当到达更深的地方时。距离外部 3.5 毫米（大约对应真皮中部）变得能够表达 CD95L（Maeda 等人，J Dermatol 2001；28：499-504），我们能够共同确定未来治疗黑色素瘤患者的可行策略。 CD95 的异位表达。除黑色素瘤外，基底细胞癌 (BCC) 是全世界最常见的皮肤肿瘤之一。 BCC 的发病机制尚不完全清楚，因此我们接下来关注这个问题，因此我们重点关注 Wnt 信号通路的信号元件 β-catenin，据报道它参与结肠癌的发病机制，为了解决这个问题，我们进行了免疫染色。 BCC 标本显示，在大约 70% 的 BCC 测试中观察到 β-连环蛋白的核易位，而其他皮肤病（如特应性皮炎、牛皮癣、鳞状细胞病）中没有观察到β-连环蛋白的核易位由于该蛋白的核易位是参与癌发生的必要条件，因此我们得出结论，β-连环蛋白参与 BCC 的发病机制，以确定哪些元素是 BCC 的致病因素。 β-连环蛋白的核转位较少。