Pygo2在经典Wnt信号通路中的作用及其研究进展

Wnt信号通路在正常组织发育以及肿瘤形成中起着重要作用.经典wnt信号通路通过促进关键蛋白β-catenin进入细胞核,与TCF/LEF结合,从而激活靶基因转录.Pygo是Wnt信号通路中新发现的成员,通过BCL9/Lgs与β-catenin结合,从而促进靶基因的转录.Pygo2的异常表达,与发育异常、肿瘤的形成有着紧密的联系.Pygo2在经典Wnt信号通路中的作用机制模式已经确定,但是与染色质重塑方面的机制有待进一步研究.最近研究发现Pygo2参与H3K56Ac,从而促进基因的表达.     

Wnt/β-catenin信号通路在肿瘤EMT现象中的作用研究进展

Wnt信号通路在胚胎发育和肿瘤的发生及转移中起着重要的作用,近年来研究发现,Wnt信号传导通路同肿瘤转移早期的EMT现象密切相关,Wnt信号转导途径可直接或间接影响EMT相关蛋白和EMT的诱发因素,本文对Wnt信号通路在肿瘤EMT发生诱导中的作用进行综述.     

Wnt信号通路为靶点的肿瘤治疗新进展

Wnt信号传导通路与肿瘤的关系一直都是近年来肿瘤研究的热点,Wnt信号通路包含许多信号成员蛋白,其中任何一个成员蛋白的突变或异常均可激活Wnt信号通路引起细胞异常增殖而导致肿瘤的发生。为此,针对Wnt信号通路不同基因靶点的高特异性基因药物开发以及肿瘤的分子诊断也相继出现。目前,Wnt信号通路为靶点的肿瘤基因治疗包括细胞膜水平、胞内通路成员蛋白水平、β-catenin水平和核内TCF/LEFs-β-catenin复合体水平。     

Wnt/β-catenin信号通路在乳腺癌中的研究进展

Wnt/β-catenin信号通路参与细胞增生分化的调节、基因表达调控和细胞迁移等重要生物过程.近年研究发现,Wnt/β-catenin信号通路的异常与乳腺癌等多种肿瘤的发生、发展密切相关.深入研究Wnt/β-catenin信号通路在乳腺癌中的作用,有助于进一步揭示乳腺癌的发生机制,为乳腺癌的防治提供新的思路及干预靶点.本文就Wnt/β-catenin通路的组成及调控机制、Wnt/β-catenin通路与乳腺癌发生、发展的关系及Wnt/β-catenin通路在乳腺癌诊治中的展望作一综述.     

Wnt在前列腺癌中的作用研究进展

经典的Wnt信号通路是多种肿瘤发生发展的一条重要通路.近年来多项研究表明,Wnt信号通路的异常激活同前列腺癌发生发展及生物学特性的改变关系密切.本文就近年来Wnt在前列腺癌中的作用研究作一综述.     

Wnt／β-catenin信号通路对神经干细胞增殖分化的影响

Wnt／β-catenin信号通路在生物发育、细胞转运、肿瘤形成及细胞凋亡等生命过程中发挥着重要的作用，它的异常活化常常与多种肿瘤的发生、发展有着密切的关系。近年的研究发现它在神经干细胞（NSCs）增殖、分化过程中的调控上有着让人欣喜的作用，因此Wnt／β-catenin信号通路对NSCs的作用更受到广泛的关注。本文就此作一篇综述。     

Wnt在前列腺癌中的作用研究进展

经典的Wnt信号通路是多种肿瘤发生发展的一条重要通路.近年来多项研究表明,Wnt信号通路的异常激活同前列腺癌发生发展及生物学特性的改变关系密切.本文就近年来Wnt在前列腺癌中的作用研究作一综述.     

Wnt在前列腺癌中的作用研究进展

经典的Wnt信号通路是多种肿瘤发生发展的一条重要通路.近年来多项研究表明,Wnt信号通路的异常激活同前列腺癌发生发展及生物学特性的改变关系密切.本文就近年来Wnt在前列腺癌中的作用研究作一综述.     

WIF-1基因与肺癌的诊断和治疗

Wnt蛋白是一组对人体生长发育和造血等过程具有重要作用的蛋白,它们所介导的信号传导通路称为Wnt信号通路,Wnt信号通路的异常激活可引起包括肺癌在内的各种肿瘤的发生。WIF-1作为一种抑癌基因,可以抑制Wnt信号通路的异常激活,从而避免肺癌的发生。而WIF-1一旦发生启动子甲基化,便会引起WIF-1表达下调,进而激活Wnt信号通路,导致肺癌的发生。因此,检测WIF-1的甲基化可以有助于肺癌的临床诊断,针对WIF-1甲基化的治疗也可作为肺癌的治疗方法之一。     

SOX7基因在乳腺癌中的研究进展

在乳腺癌等一些人类肿瘤的研究中发现,SOX7基因极有可能是一个抑癌基因.SOX7基因抑癌作用的机制可能是通过调节Wnt/β-catenin信号通路介导的转录过程来完成的,而异常的Wnt/β-catenin 信号通路则有可能通过调控其下游的靶向基因Cyclin D1等来发挥其作用,使细胞的异常增生活动无法进行下去,从而发挥其肿瘤抑制的功能.本文就目前乳腺癌中SOX7基因的作用及其与之密切相关的β-catenin、Cyclin D1基因的研究现状作一综述.     

毛囊干细胞定向分化过程中Wnt信号通路介导的基因调控

皮肤的毛囊干细胞具有自我复制以及多向分化潜能,在毛囊形态发育和定向分化过程中,Wnt信号通路起决定性作用。参与这条信号通路的重要蛋白质,如Wnt蛋白、Frizzled、B—catenin、GSK313、APC、Axin等研究相对较早,且颇为深入。但对于这条通路下游的调节因子,尤其是细胞核内关键性转录因子Tcf3、Lef1,以及它们所调控的一些重要基因c—myc、eyelinDl等的研究仍处于起步阶段。本文就Wnt信号通路介导的基因调节毛囊干细胞定向分化的研究现状进行综述．为构建组织工程皮肤提供理论参考。     

Yes相关蛋白通过Wnt/β-catenin信号通路调控软骨细胞Sox9表达的研究

目的研究Yes相关蛋白（Yes?associated protein, YAP）通过Wnt/β?catenin信号通路调控软骨细胞Sox9表达的机制。方法用siRNA分别沉默YAP基因和Lats1基因来调控YAP的活性,通过Real?time PCR检测软骨特异性基因和Wnt/β?catenin信号通路下游基因的表达;通过Western Blot检测GSK3β的磷酸化水平、活化β?catenin的蛋白水平以及Sox9的蛋白水平;并通过阿利新蓝染色检测软骨细胞外基质的分泌情况。用siRNA沉默YAP基因后,再用氯化锂干预细胞,通过Western Blot检测Sox9的表达和GSK3β的磷酸化水平。结果沉默YAP基因后,磷酸化GSK3β和活化β?catenin的蛋白水平减少,c?Myc和Nanog基因表达减少,Sox9、Col2和Aggrecan基因表达升高,并且软骨细胞分泌基质增多;沉默Lats1基因后,磷酸化GSK3β和活化β?catenin的蛋白水平增加,c?Myc和Nanog基因表达上调,Sox9、Col2和Aggre?can基因表达减少,并且软骨细胞分泌基质减少。此外,氯化锂可以阻断沉默YAP引起的Sox9表达上调。结论 YAP通过Wnt/β?catenin信号通路调控软骨细胞Sox9的表达。     

Where Wnts Went: The Exploding Field of Lrp5 and Lrp6 Signaling in Bone

Wnt signaling has emerged as a central regulator of skeletal modeling and remodeling. Loss‐ or gain‐of‐function mutations in two Wnt co‐receptors, Lrp5 and (more recently) Lrp6, have drawn attention to the importance of the Wnt pathway in bone biology. This review summarizes our current understanding of how the Wnt pathway operates on bone and the implications this has for skeletal physiology and drug discovery. Over the past 9 yr, rapid advances have been made in our understanding of the cellular targets for Wnt signaling and of the important regulatory molecules in this metabolic pathway. Both canonical and noncanonical signaling pathways seem to be important for mediating the effects of Wnt in bone. A rapidly expanding catalog of genetically engineered mice has been used to establish the importance of downstream effector molecules (such as β‐catenin) in the Wnt pathway, as well as the critical role of endogenous inhibitors of Wnt signaling (such as Dkk1 and sclerostin) in bone metabolism. Indeed, regulation of sclerostin in osteocytes is emerging as an important final pathway for regulating bone anabolism in response to diverse trophic stimuli, from mechnotransduction to the anabolic actions of PTH. From the outset, it had been assumed that the effects of Wnt signaling in bone were caused by direct actions in osteoblast precursors, osteoblasts, and osteocytes. However, startling recent findings have challenged this view and suggest that a key target, at least in mice, is the duodenal enterochromaffin cell. There, Wnt signaling transduced by Lrp5 regulates serotonin synthesis, which acts in an endocrine fashion to regulate bone cell metabolism. It will take time to reconcile this new information with the considerable body of information we already have regarding the actions of Wnt in bone. The Wnt pathway has rapidly emerged as a therapeutic target for drug discovery. Neutralizing antibodies and small‐molecule inhibitors of endogenous Wnt inhibitors have shown early promise as bone anabolic agents. However, given the central role of the Wnt pathway in regulating growth and development in extraskeletal tissues, as well as our still rudimentary understanding of how this signaling cascade actually affects bone metabolism, considerable work will be needed to ensure the safety of these new therapies.     

雌激素通过氯通道影响骨质疏松的研究进展

骨质疏松是一种严重损害老年人的疾病,而氯通道可以驱动成骨细胞的矿化、调节精细骨结构。研究发现,雌激素可激活氯通道并参与骨形成功能,提示氯通道可能是雌激素调节骨形成的重要靶点。Wnt信号通路在调节骨形成中发挥关键作用,实验表明雌激素可激活Wnt信号通路,抑制或下调Cl C-3氯通道阻断Wnt信号通路的激活,提示Cl C-3氯通道可能通过调控Wnt信号途径介导雌激素促进骨形成。该文就氯通道、雌激素及Wnt信号通路与骨质疏松关系的研究进展作一综述。     

Gene array analysis of Wnt-regulated genes in C3H10T1/2 cells

Wnt/beta-catenin signaling is involved in a large variety of modeling and remodeling processes including cell polarity, cell differentiation, and cell migration. Recently, a role of the Wnt pathway in bone biology has been demonstrated. However, the precise mechanism by which Wnt proteins regulate bone formation still remains to be elucidated. We have previously shown that the Wnt pathway mediates induction of alkaline phosphatase, an osteoblast differentiation marker, in the pluripotent mesenchymal cells C3H10T1/2. In the present study, we performed a genome-wide expression analysis using Affymetrix oligonucleotide chips to determine the Wnt3a-induced gene expression profile in C3H10T1/2 cells. The expression profiles of 447 Wnt3a-regulated genes, classified into distinct functional families, are presented here. Our data reveal that Wnt3a regulates several genes that are involved in osteoblast and adipocyte differentiation. Importantly, Wnt3a induces the expression of osteoprotegerin by a beta-catenin dependent mechanism indicating that the Wnt pathway may also affect osteoclastogenesis. Through the analysis of our expression profiling data, we have established a TaqMan panel as a tool to rapidly compare the expression profiles of a specific set of genes induced by distinct stimuli acting in the Wnt/beta-catenin pathway. Using the TaqMan panel, we have compared the gene expression profiles induced by Wnt1, Wnt2, and Wnt3a in C3H10T1/2 cells, and also by two different GSK-3beta inhibitors: LiCl and SB216773. Our data show that Wnt1 and Wnt3a act in a similar manner, distinct from Wnt2. Finally, we found that LiCl and SB216773 displayed different profiles in the TaqMan panel evidencing their distinct inhibitory action toward GSK-3beta. Overall, data presented herein will aid further understanding of the involvement of the Wnt signaling pathway in its regulation of osteoblast and adipocyte differentiation and function and, in addition, will enhance current knowledge of the Wnt signaling pathway itself.     

Ultrasound-induced activation of Wnt signaling in human MG-63 osteoblastic cells

The benefit from an ultrasound (US) exposure for fracture healing has been clearly shown. However, the molecular mechanisms behind this effect are not fully known. Recently, the canonical Wnt signaling pathway has been recognized as one of the essential regulators of osteoblastogenesis and bone mass, and thereby considered crucial for bone health. Mechanical loading and fluid shear stress have been reported to activate the canonical Wnt signaling pathway in bone cells, but previous reports on the effects of therapeutic US on Wnt signaling in general or in bone, in particular, have not been published yet. Therefore, activation of Wnt signaling pathway was assayed in human osteoblastic cells, and indeed, this pathway was found to be activated in MG-63 cells through the phosphoinositol 3-kinase/Akt (PI3K/Akt) and mTOR cascades following a single 10 min US exposure (2 W, 1.035 MHz). In addition to the reporter assay results, the Wnt pathway activation was also observed as nuclear localization of β-catenin. Wnt activation showed also temperature dependence at elevated temperatures, and the expression of canonical Wnt ligands was induced under the thermal exposures. However, existence of a specific, non-thermal US component was evident as well, perhaps evidence of a potential dual action of therapeutic US on bone. Neither US nor heat exposures affected cell viability in our experiments. In summary, this is the first study to report that Wnt signaling cascade, important for osteoblast function and bone health, is one of the pathways activated by therapeutic US as well as by hyperthermia in human osteoblastic cells. Our results provide evidence for the potential molecular mechanisms behind the beneficial effects of US on fracture healing. Combinations of US, heat, and possible pharmacological treatment could provide useful flexibility for clinical cases in treating various bone disorders.     

Targeting the Wnt signaling pathway to augment bone formation

Recent discoveries in humans and mice have revealed that the Wnt (Wingless and Int-1) signaling pathway is responsible for a complex array of functions in maintaining bone homeostasis. The Wnt proteins are key modulators of mesenchymal lineage specification and regulate most aspects of osteoblast physiology and postnatal bone acquisition by controlling the differentiation and activity of osteoblasts and osteoclasts. Initial reports have indicated that activators of Wnt signaling are potent promoters of osteogenesis; however, systemic hyperactivation of the canonical Wnt pathway could potentially accelerate neoplastic transformation and subsequent tumor growth. Alternatively, recent investigations of natural soluble antagonists of Wnt signaling in bone suggest the possibilities of bone-specific therapies targeting the negative regulators of Wnt pathway, especially sclerostin. With this new knowledge, novel pharmacologic interventions that alter Wnt signaling are being evaluated for the management of osteoporosis. In this article, we briefly describe the Wnt signaling elements, their characterized role in bone, and summarize the current knowledge on the potential to enhance bone formation through the manipulation of Wnt signaling antagonists.     

P120连环蛋白/转录抑制因子Kaiso与Wnt信号通路在肿瘤发病机制中的作用

异常的经典的Wnt信号通路的激活可以促进肿瘤的发生。P120连环蛋白/转录抑制因子Kaiso对Wnt信号通路的靶基因具有调控作用,影响Wnt信号通路的活动,从而影响肿瘤发生的过程。