Wnt/β-catenin通路在人类纤维样疾病中的作用及其作为治疗靶点的资格

Molecular and cellular therapies Pub Date : 2015-01-30 eCollection Date: 2015-01-01
Maria Vittoria Enzo, Marco Rastrelli, Carlo Riccardo Rossi, Uros Hladnik, Daniela Segat
{"title":"Wnt/β-catenin通路在人类纤维样疾病中的作用及其作为治疗靶点的资格","authors":"Maria Vittoria Enzo, Marco Rastrelli, Carlo Riccardo Rossi, Uros Hladnik, Daniela Segat","doi":"","DOIUrl":null,"url":null,"abstract":"<p><p>The canonical Wnt signaling pathway is involved in a variety of biological processes like cell proliferation, cell polarity, and cell fate determination. This pathway has been extensively investigated as its deregulation is linked to different diseases, including various types of cancer, skeletal defects, birth defect disorders (including neural tube defects), metabolic diseases, neurodegenerative disorders and several fibrotic diseases like desmoid tumors. In the \"on state\", beta-catenin, the key effector of Wnt signaling, enters the nucleus where it binds to the members of the TCF-LEF family of transcription factors and exerts its effect on gene transcription. Disease development can be caused by direct or indirect alterations of the Wnt/β-catenin signaling. In the first case germline or somatic mutations of the Wnt components are associated to several diseases such as the familial adenomatous polyposis (FAP) - caused by germline mutations of the tumor suppressor adenomatous polyposis coli gene (APC) - and the desmoid-like fibromatosis, a sporadic tumor associated with somatic mutations of the β-catenin gene (CTNNB1). In the second case, epigenetic modifications and microenvironmental factors have been demonstrated to play a key role in Wnt pathway activation. The natural autocrine Wnt signaling acts through agonists and antagonists competing for the Wnt receptors. Anomalies in this regulation, whichever is their etiology, are an important part in the pathogenesis of Wnt pathway linked diseases. An example is promoter hypermethylation of Wnt antagonists, such as SFRPs, that causes gene silencing preventing their function and consequently leading to the activation of the Wnt pathway. Microenvironmental factors, such as the extracellular matrix, growth factors and inflammatory mediators, represent another type of indirect mechanism that influence Wnt pathway activation. A favorable microenvironment can lead to aberrant fibroblasts activation and accumulation of ECM proteins with subsequent tissue fibrosis that can evolve in fibrotic disease or tumor. Since the development and progression of several diseases is the outcome of the Wnt pathway cross-talk with other signaling pathways and inflammatory factors, it is important to consider not only direct inhibitors of the Wnt signaling pathway but also inhibitors of microenvironmental factors as promising therapeutic approaches for several tumors of fibrotic origin. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"3 ","pages":"1"},"PeriodicalIF":0.0000,"publicationDate":"2015-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452070/pdf/","citationCount":"0","resultStr":"{\"title\":\"The Wnt/β-catenin pathway in human fibrotic-like diseases and its eligibility as a therapeutic target.\",\"authors\":\"Maria Vittoria Enzo, Marco Rastrelli, Carlo Riccardo Rossi, Uros Hladnik, Daniela Segat\",\"doi\":\"\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The canonical Wnt signaling pathway is involved in a variety of biological processes like cell proliferation, cell polarity, and cell fate determination. This pathway has been extensively investigated as its deregulation is linked to different diseases, including various types of cancer, skeletal defects, birth defect disorders (including neural tube defects), metabolic diseases, neurodegenerative disorders and several fibrotic diseases like desmoid tumors. In the \\\"on state\\\", beta-catenin, the key effector of Wnt signaling, enters the nucleus where it binds to the members of the TCF-LEF family of transcription factors and exerts its effect on gene transcription. Disease development can be caused by direct or indirect alterations of the Wnt/β-catenin signaling. In the first case germline or somatic mutations of the Wnt components are associated to several diseases such as the familial adenomatous polyposis (FAP) - caused by germline mutations of the tumor suppressor adenomatous polyposis coli gene (APC) - and the desmoid-like fibromatosis, a sporadic tumor associated with somatic mutations of the β-catenin gene (CTNNB1). In the second case, epigenetic modifications and microenvironmental factors have been demonstrated to play a key role in Wnt pathway activation. The natural autocrine Wnt signaling acts through agonists and antagonists competing for the Wnt receptors. Anomalies in this regulation, whichever is their etiology, are an important part in the pathogenesis of Wnt pathway linked diseases. An example is promoter hypermethylation of Wnt antagonists, such as SFRPs, that causes gene silencing preventing their function and consequently leading to the activation of the Wnt pathway. Microenvironmental factors, such as the extracellular matrix, growth factors and inflammatory mediators, represent another type of indirect mechanism that influence Wnt pathway activation. A favorable microenvironment can lead to aberrant fibroblasts activation and accumulation of ECM proteins with subsequent tissue fibrosis that can evolve in fibrotic disease or tumor. Since the development and progression of several diseases is the outcome of the Wnt pathway cross-talk with other signaling pathways and inflammatory factors, it is important to consider not only direct inhibitors of the Wnt signaling pathway but also inhibitors of microenvironmental factors as promising therapeutic approaches for several tumors of fibrotic origin. </p>\",\"PeriodicalId\":90271,\"journal\":{\"name\":\"Molecular and cellular therapies\",\"volume\":\"3 \",\"pages\":\"1\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2015-01-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452070/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular and cellular therapies\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2015/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular and cellular therapies","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2015/1/1 0:00:00","PubModel":"eCollection","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

摘要

典型的Wnt信号通路参与多种生物过程,如细胞增殖、细胞极性和细胞命运决定。这一途径已被广泛研究,因为它的失调与不同的疾病有关,包括各种类型的癌症、骨骼缺陷、出生缺陷疾病(包括神经管缺陷)、代谢性疾病、神经退行性疾病和一些纤维化疾病,如硬纤维瘤。在“开”状态下,Wnt信号的关键效应因子β -catenin进入细胞核,与TCF-LEF转录因子家族成员结合,对基因转录发挥作用。疾病的发展可由Wnt/β-连环蛋白信号的直接或间接改变引起。在第一种情况下,Wnt成分的种系或体细胞突变与几种疾病有关,如家族性腺瘤性息肉病(FAP)——由肿瘤抑制性腺瘤性息肉病大肠基因(APC)的种系突变引起——和纤维瘤样病,一种与β-连环蛋白基因(CTNNB1)的体细胞突变相关的散发性肿瘤。在第二种情况下,表观遗传修饰和微环境因素已被证明在Wnt通路激活中发挥关键作用。自然自分泌的Wnt信号通过激动剂和拮抗剂竞争Wnt受体发挥作用。无论其病因如何,这一调控的异常都是Wnt通路相关疾病发病机制的重要组成部分。一个例子是Wnt拮抗剂(如SFRPs)的启动子超甲基化,导致基因沉默,阻止其功能,从而导致Wnt通路的激活。微环境因素,如细胞外基质、生长因子和炎症介质,是影响Wnt通路激活的另一种间接机制。有利的微环境可导致成纤维细胞异常激活和ECM蛋白的积累,从而导致纤维化疾病或肿瘤的组织纤维化。由于一些疾病的发生和进展是Wnt通路与其他信号通路和炎症因子相互作用的结果,因此考虑Wnt信号通路的直接抑制剂和微环境因子抑制剂作为几种纤维化源性肿瘤的有希望的治疗方法是很重要的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

The Wnt/β-catenin pathway in human fibrotic-like diseases and its eligibility as a therapeutic target.

The Wnt/β-catenin pathway in human fibrotic-like diseases and its eligibility as a therapeutic target.

The Wnt/β-catenin pathway in human fibrotic-like diseases and its eligibility as a therapeutic target.

The canonical Wnt signaling pathway is involved in a variety of biological processes like cell proliferation, cell polarity, and cell fate determination. This pathway has been extensively investigated as its deregulation is linked to different diseases, including various types of cancer, skeletal defects, birth defect disorders (including neural tube defects), metabolic diseases, neurodegenerative disorders and several fibrotic diseases like desmoid tumors. In the "on state", beta-catenin, the key effector of Wnt signaling, enters the nucleus where it binds to the members of the TCF-LEF family of transcription factors and exerts its effect on gene transcription. Disease development can be caused by direct or indirect alterations of the Wnt/β-catenin signaling. In the first case germline or somatic mutations of the Wnt components are associated to several diseases such as the familial adenomatous polyposis (FAP) - caused by germline mutations of the tumor suppressor adenomatous polyposis coli gene (APC) - and the desmoid-like fibromatosis, a sporadic tumor associated with somatic mutations of the β-catenin gene (CTNNB1). In the second case, epigenetic modifications and microenvironmental factors have been demonstrated to play a key role in Wnt pathway activation. The natural autocrine Wnt signaling acts through agonists and antagonists competing for the Wnt receptors. Anomalies in this regulation, whichever is their etiology, are an important part in the pathogenesis of Wnt pathway linked diseases. An example is promoter hypermethylation of Wnt antagonists, such as SFRPs, that causes gene silencing preventing their function and consequently leading to the activation of the Wnt pathway. Microenvironmental factors, such as the extracellular matrix, growth factors and inflammatory mediators, represent another type of indirect mechanism that influence Wnt pathway activation. A favorable microenvironment can lead to aberrant fibroblasts activation and accumulation of ECM proteins with subsequent tissue fibrosis that can evolve in fibrotic disease or tumor. Since the development and progression of several diseases is the outcome of the Wnt pathway cross-talk with other signaling pathways and inflammatory factors, it is important to consider not only direct inhibitors of the Wnt signaling pathway but also inhibitors of microenvironmental factors as promising therapeutic approaches for several tumors of fibrotic origin.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信