SFRP基因甲基化与消化系肿瘤相关性的研究进展

DNA启动子异常甲基化是人类基因组一种最常见的表观遗传学修饰改变,与肿瘤的发生发展及预后密切相关.分泌型卷曲相关蛋白(secreted frizzled-related proteins,SFRPs)作为Wnt信号通路的拮抗因子,在多种肿瘤中常由于其启动子的高甲基化而致该基因的表达沉默,从而减弱对Wnt信号通路的抑制作用,使得Wnt信号通路异常激活,促进了肿瘤的发生与发展.本文就SFRP基因甲基化在消化系肿瘤中的研究作一综述.     

Wnt/β-catenin信号通路在结直肠癌中的研究进展

Wnt/β-catenin信号通路(Wnt经典信号通路)是目前Wnt信号通路中研究较为深入的一条分支.他在从果蝇到人类的胚胎发育、组织器官形成以及肿瘤发生等重大事件中扮演重要角色.结直肠癌具有发病率和死亡率高的特征,故对其机制进行深入地研究十分重要.结直肠癌的分子生物学研究经常可以发现Wnt/β-catenin信号通路的异常激活.因此,研究Wnt/β-catenin信号通路可能为临床结直肠癌的治疗提供新的潜在靶点.通过回顾近年来相关文献,就Wnt/β-catenin信号通路和其与结直肠癌的关系及以Wnt/β-catenin信号通路为靶点的抗结直肠肿瘤研究做一综述.     

Wnt诱导分泌蛋白-1与器官纤维化

Wnt信号通路参与调节机体发育诸多过程,Wnt信号通路异常激活可以导致肿瘤、纤维增生等疾病过程的发生。Wnt诱导分泌蛋白-1(WISP-1)是Wnt信号通路活化后的下游靶基因之一,最近研究表明WISP-1与肺、心脏、肝等脏器纤维化相关,此文就WISP-1与器官纤维化的研究进展作一综述。     

Wnt/β-catenin通路与消化道肿瘤发生发展的关系

Wnt/β-catenin信号通路是调节胚胎发育及细胞增殖的重要途径之一,其异常激活会影响细胞正常的生长、增殖及迁移,在消化道肿瘤的发生发展中扮演着重要角色。本文对Wnt/β-catenin信号通路在食管癌、胃癌、结直肠癌等发病机制中的影响进行综述,探讨Wnt/β-catenin信号通路与消化道肿瘤发生发展的关系,为消化道肿瘤的靶向治疗提供新的研究思路。     

Wnt/β-catenin信号通路与肝癌发生发展的研究进展

已有研究表明肝癌的发生发展与多种信号通路有关.其中, Wnt配体/β-连环蛋白(Wnt/β-catenin)信号通路参与肝脏疾病进展的所有阶段,从最初的肝损伤到炎症、纤维化、肝硬化以及肿瘤的发生及进展均有所参与.异常的Wnt/β-catenin信号会促进包括癌症在内的不同肝脏疾病的发生和进展.在这篇综述中,我们将在介绍Wnt/β-catenin信号通路的激活、生物学功能及调控机制的基础上,讨论Wnt/β-catenin信号通路在肝癌的发生和进展的中的作用,并将对目前小分子抑制剂、中药提取物及微小RNAs(microRNAs,miRNAs)等能够抑制Wnt/β-catenin信号通路的相关因子进行阐述,为肝癌的基础与临床研究提供参考.     

舒林酸对人胰腺癌细胞PANC1增殖凋亡及Wnt通路的影响

Wnt／β-catenin信号通路直接影响胰腺癌细胞的增殖、分化和迁移。研究发现,在许多肿瘤组织中Wnt／β-catenin信号通路异常激活。3-catenin在胰腺上皮内瘤变（pancreatic intraepithelial neoplasia,PanIN）及胰腺癌蛋白的核内高度积聚㈨。文献报道,     

Wnt抑制因子SFRP基因甲基化与白血病的关系

近年来研究发现,Wnt信号通路在胚胎发育、细胞行为、基因表达、肿瘤增生以及细胞凋亡等生命过程中发挥重要作用;其异常激活会促进细胞过度生长、增殖和分化,与白血病及其相关疾病的发生和发展有着密切关系。Wnt通路抑制因子分泌型卷曲相关蛋白（SFRP）在结构上与卷曲蛋白（Fz）受体极为相似,与Fz受体竞争结合Wnt从而抑制Wnt通路的活动。但当SFRP异常甲基化导致表达沉默时,     

以β-catenin为中心的Wnt信号通路在消化道肿瘤发生中的作用

Wnt家族基因编码一组糖蛋白信号分子,这些糖蛋白分子激活的信号通路在人类不同肿瘤中的作用是相互交织的.β-catenin是Wnt信号通路正向调节重要效应物,其胞质内降解的失调及核内累积激活一系列靶基因的转录导致肿瘤的发生.这个过程中许多成分质和量的改变与临床不同病理指标有关,了解这条通路在肿瘤发生过程中具体的分子机制有助于为临床诊断提供依据,为早期干预治疗提供方法.     

Wnt信号通路与消化道肿瘤

Wnt信号通路(Wnt signaling pathway)是调控细胞生长、发育和分化的关键通路之一[1].最早关于Wnt信号通路的了解来自对致癌病毒和果蝇发育机制的研究.1982年,在小鼠乳腺癌中发现了Wnt基因,由于该基因激活需依赖小鼠乳腺癌相关病毒基因的插入(insertion),因此,最初被命名为Int-1癌基因.随后的研究表明,Int-1基因在小鼠正常胚胎的发育中起重要作用,其编码的蛋白在细胞间传递生长和发育的信息,控制胚胎轴向的正常发育,其相当于果蝇的无翅基因(Wingless gene),因此,将Wingless与Int-1两词合并称为Wnt基因.近年来的研究表明,Wnt细胞信号通路成分的突变与人类多种肿瘤的发生、发展密切相关.本文着重就Wnt信号通路与人类消化道肿瘤关系的研究进展作一综述.     

Wnt信号转导通路与肝纤维化关系的研究现况

阻断该通路可以 Wnt 信号转导通路是近年来分子生物学、细抑制癌细胞的增殖和诱导凋亡.胞生物学和肿瘤研究中的一大热点,其参与调 控细胞分化、癌变、凋亡及机体免疫、应激 等多种病理生理过程.目前许多关于癌症方面 的研究均已证实,阻断Wnt 信号通路可以诱导 癌症细胞的凋亡.肝纤维化的发生与多种信号 通路的激活相关,有研究...     

The Wnt signaling pathway and its role in tumor development

Cancer development depends on the aberrant activation of signal transduction pathways that control cell growth and survival and play important roles in normal embryonic development. This review will focus on one of the most powerful pathways, the canonical Wnt signal transduction cascade, which has been originally described in vertebrate and non-vertebrate embryogenesis and subsequently associated with the development of a multitude of different tumor types, mainly of gastrointestinal origin. In recent years, a variety of novel interacting components and functions have been identified in the Wnt pathway revealing not only the complexity of Wnt signaling but also its potency. Here we will concentrate on the role of the Wnt pathway in cancer development with emphasis placed on the molecular defects known to promote neoplastic transformation in humans and in animal models.     

Signal transduction,calcium and acute pancreatitis

Evidence consistently suggests that the earliest changes of acute pancreatitis are intracellular, the hallmark of which is premature intracellular activation of digestive zymogens, accompanied by disruption of normal signal transduction and secretion. Principal components of physiological signal transduction include secretagogueinduced activation of G-protein-linked receptors, followed by generation of inositol 1,4,5-trisphosphate, nicotinic acid adenine dinucleotide phosphate and cyclic ADP-ribose. In response, calcium is released from endoplasmic reticulum terminals within the apical, granular pole of the cell, where calcium signals are usually contained by perigranular mitochondria, in turn responding by increased metabolism. When all three intracellular messengers are administered together, even at threshold concentrations, dramatic potentiation results in sustained, global, cytosolic calcium elevation. Prolonged, global elevation of cytosolic calcium is also induced by hyperstimulation, bile salts, alcohol and fatty acid ethyl esters, and depends on continued calcium entry into the cell. Such abnormal calcium signals induce intracellular activation of digestive enzymes, and of nuclear factor κB, as well as the morphological changes of acute pancreatitis. Depletion of endoplasmic reticulum calcium and mitochondrial membrane potential may contribute to further cell injury. This review outlines current understanding of signal transduction in the pancreas, and its application to the pathophysiology of acute pancreatitis.     

Wnt信号通路相关分子在肝纤维化中的表达水平变化及其意义

目的 观察Wnt信号通路相关分子在实验性肝纤维化组织中表达水平的变化.探讨其在肝纤维化发生中的作用.方法 建立大鼠肝纤维化动物模型.用Wnt信号通路PCR array功能基因芯片观察Wnt信号通路相关分子在肝纤维化模型中表达水平的变化.以模型组较正常组表达上调或下调2倍为差异表达基因;利用免疫组化及Western印迹观察平滑肌肌动蛋白、Wnt4、Frizzled2、β-钙粘蛋白在肝纤维化组织表达水平的变化.结果 芯片检测发现共有36条基因发生了显著改变,模型组较正常组上调2倍的基因有25个,上调基因主要包括Wnt5a类基因,如Wnt4、Wnt5a、Wnt11等,分别上调了13.9、16.5和2.17倍;较正常组下调2倍的基因有11个,主要为Wnt1、Wnt3等.分别下调了2.32、2.15倍.免疫组化及Western印迹检测发现模型组肝组织Wnt4、Frizzled2的表达水平较正常组显著上升,而磷酸化的β-钙粘蛋白的表达水平下降.结论 经典及非经典Wnt信号通路均可能参与了实验性肝纤维化的发生机制.     

miRNAs与Wnt通路调节食管癌的发生

食管癌是最常见的消化道恶性肿瘤之一,其发生机制多样,死亡率高、预后差。miRNA是一类非编码单链RNA分子,调控细胞分化、增殖及凋亡,与肿瘤的启动和进展密切相关。Wnt信号通路通过激活下游信号传导途径,实现细胞间或自体细胞的信号交流,广泛存在于胚胎发育、间充质细胞转换和恶性肿瘤的形成和发展过程中。食管癌组织中特异表达的miRNAs通过调节Wnt信号通路促进食管癌的发生、发展。本文综述了食管癌中与Wnt通路相关的miRNAs,并阐述其作用机制。     

Evidence that the cysteine-rich domain of Drosophila Frizzled family receptors is dispensable for transducing Wingless

Members of the Frizzled family of serpentine transmembrane receptors are required to transduce Wingless/Int (Wnt) signals and contain in their N-terminal regions a conserved Wnt-binding cysteine-rich domain (CRD). Each CRD has specific affinities for particular Wnts, and it is generally believed that signal transduction depends on the strength of this interaction. Here, we report in vivo evidence that the CRD is dispensable for Frizzled family receptors to transduce Wingless (Wg), the primary Wnt signal in Drosophila. Thus, we infer that signal transduction does not require binding of Wg to the CRD, but instead depends on interactions between Wg and other portions of the receptor, or other proteins of the receptor complex.     

Dishevelled interacts with the DIX domain polymerization interface of Axin to interfere with its function in down-regulating β-catenin

Wnt/β-catenin signaling controls numerous steps in normal animal development and can also cause cancer if inappropriately activated. In the absence of Wnt, β-catenin is targeted continuously for proteasomal degradation by the Axin destruction complex, whose activity is blocked upon Wnt stimulation by Dishevelled, which recruits Axin to the plasma membrane and assembles it into a signalosome. This key event during Wnt signal transduction depends on dynamic head-to-tail polymerization by the DIX domain of Dishevelled. Here, we use rescue assays in Drosophila tissues and functional assays in human cells to show that polymerization-blocking mutations in the DIX domain of Axin disable its effector function in down-regulating Armadillo/β-catenin and its response to Dishevelled during Wnt signaling. Intriguingly, NMR spectroscopy revealed that the purified DIX domains of the two proteins interact with each other directly through their polymerization interfaces, whereby the same residues mediate both homo- and heterotypic interactions. This result implies that Dishevelled has the potential to act as a "natural" dominant-negative, binding to the polymerization interface of Axin's DIX domain to interfere with its self-assembly, thereby blocking its effector function.     

Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells

Salinomycin, an antibiotic potassium ionophore, has been reported recently to act as a selective breast cancer stem cell inhibitor, but the biochemical basis for its anticancer effects is not clear. The Wnt/β-catenin signal transduction pathway plays a central role in stem cell development, and its aberrant activation can cause cancer. In this study, we identified salinomycin as a potent inhibitor of the Wnt signaling cascade. In Wnt-transfected HEK293 cells, salinomycin blocked the phosphorylation of the Wnt coreceptor lipoprotein receptor related protein 6 (LRP6) and induced its degradation. Nigericin, another potassium ionophore with activity against cancer stem cells, exerted similar effects. In otherwise unmanipulated chronic lymphocytic leukemia cells with constitutive Wnt activation nanomolar concentrations of salinomycin down-regulated the expression of Wnt target genes such as LEF1, cyclin D1, and fibronectin, depressed LRP6 levels, and limited cell survival. Normal human peripheral blood lymphocytes resisted salinomycin toxicity. These results indicate that ionic changes induced by salinomycin and related drugs inhibit proximal Wnt signaling by interfering with LPR6 phosphorylation, and thus impair the survival of cells that depend on Wnt signaling at the plasma membrane.     

Oncogenic Wnt3a is a promising sensitive biomarker for monitoring hepatocarcinogenesis

Background: The effective treatment for hepatocellular carcinoma(HCC) depends on early diagnosis. Previously, the abnormal expression of Wnt3a as the key signaling molecule in the Wnt/β-catenin pathway was found in HCC cells and could be released into the circulation. In this study, we used rat model of hepatocarcinogenesis to dynamically investigate the alteration of oncogenic Wnt3a and to explore its early monitor value for HCC. Methods: Sprague-Dawley rats(SD) were fed with diet 2-fluorenylac...     

Small-molecule synergist of the Wnt/beta-catenin signaling pathway

The Wnt/beta-catenin signaling pathway regulates cell fate and behavior during embryogenesis, adult tissue homeostasis, and regeneration. When inappropriately activated, the pathway has been linked to colorectal cancer and melanoma, and when attenuated it may contribute to Alzheimer's disease and osteoporosis. Small molecules that modulate Wnt signaling will likely provide new insights into the regulation of this key developmental pathway and ultimately provide pharmacological agents to control Wnt signaling in vivo. To this end, we screened a library of 100,000 small molecules for activity in a cell-based assay of Wnt/beta-catenin signaling and discovered a purine derivative, QS11, that synergizes with Wnt-3a ligand in the activation of Wnt/beta-catenin signal transduction. Through affinity chromatography and subsequent functional assays, we showed that QS11 binds and inhibits the GTPase activating protein of ADP-ribosylation factor 1 (ARFGAP1), suggesting that QS11 modulates Wnt/beta-catenin signaling through an effect on protein trafficking. Consistent with its function as an ARFGAP inhibitor, QS11 inhibits migration of ARFGAP overexpressing breast cancer cells.