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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670856/
• 关键词: CD95 ligrand(CD95L); ultraviolet B light(UVB); apoptosis; CD95(Fas; APO-a); β-catenin; melanoma; basal call caracinoma(BCC); 遺伝子導入; Fas; Fasリガンド; 前臨床的遺伝子治療; UVB; CD95; CD95 ligrand(CD95L); ultraviolet B light(UVB); apoptosis; CD95(Fas; APO-a); β-catenin; melanoma; basal call caracinoma(BCC); 遺伝子導入; Fas; Fasリガンド; 前臨床的遺伝子治療; UVB; CD95

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涉及紫外线B光（UV）诱导的表皮细胞凋亡的机制。理论背景为1）紫外线被认为是非黑色素瘤皮肤癌的潜在致癌物，包括鳞状ELL癌（SCC），基本细胞癌（BCC），2）紫外线众所周知，众所周知，众所周知，uv可有效诱导表皮细胞的细胞凋亡，例如伴有角膜生素细胞和梅兰素的细胞。基于这些迄今为止有关伴膜细胞凋亡的知识，我们认为是否可以使用有关凋亡的知识来操纵疗法，例如针对癌症的疗法。因此，为了解决这一问题，我们首先专注于人工诱导黑色素瘤细胞的凋亡。以前，我们可以表达高级阶段的黑色素瘤细胞急剧表达CD95配体（CD95L/APO-1L/FASL）。由于包括免疫能力细胞在内的几乎所有类型的细胞都表达CD95（Maeda等，Br J Dermatol 1998; 139：198-206），黑色素瘤可能会反攻击……更多的E细胞通过CD95/CD95L交叉链接诱导其凋亡。为了利用这些知识，我们首先感兴趣的是，当我们在黑色素瘤细胞上引入CD95表达时，我们是否可以诱导表达CD95L的黑色素瘤细胞凋亡。答案是“是”，正如我们发表的那样，CD95在表达CD95L的黑色素瘤上的异位表达导致这些细胞的急剧凋亡。这意味着这种策略在黑色素瘤WELYPY中的未来理论实用程序。尽管上述研究清楚地表明CD95引入CD95L+黑色素瘤细胞的有效性，但我们应该知道何时打开黑色素瘤CD95L。因此，我们接下来使用患者的标本进行了分析，以表达CD95L的表达，因此发现，当从外部到达3.5毫米的深度（相应的大约中间的真皮）能够表达CD95L（Maeda等人，J Dermatol 2001; 28：499-504）。总之，我们能够通过CD95.Besides黑色素瘤，碱性细胞癌（BCC）的生态表达来确定未来可行的策略，是全球最常遇到的皮肤病性肿瘤之一。由于BCC的发病机理尚不完全清楚，因此我们接下来关注这个问题。因此，我们集中了β-catenin，这是Wnt信号途径的信号传导元件，据报道与结肠癌的发病机理有关。为了解决这个问题，我们对BCC标本进行了免疫染色，表明在大约70％的BCC测试中观察到β-catenin的核易位，而其他皮肤病（例如特应性皮肤炎，牛皮癣，鳞状细胞癌）的非其他皮肤病在很多方面产生了阳性信号。由于该蛋白的核易位是参与致癌的必需条件，因此我们得出结论，B-catenin参与BCC的发病机理。需要进一步分析以确定哪些元素是β-catenin的核易位。较少的