肿瘤中Axin表达减少的机制及其研究进展

Wnt信号转导通路是调控机体发育过程中细胞形状、运动、黏附、增殖、分化、癌变的重要途径之一.轴蛋白Axin是一种体轴发育抑制因子,作为构架蛋白在Wnt信号转导途径中起关键作用,它通过不同的机制调节β连环蛋白(β-catenin)的磷酸化和稳定性.Axin通过与结肠腺瘤性息肉病构架蛋白、糖原合酶激酶3β、β-cateni...     

持续负载压力对髓核细胞凋亡及Wnt/β-catenin信号通路的影响

文题释义：细胞凋亡：是指为维持内环境稳定,由基因控制的细胞自主的有序的死亡。细胞凋亡与细胞坏死不同,细胞凋亡不是一件被动的过程,而是主动过程,它涉及一系列基因的激活、表达以及调控等作用;它并不是病理条件下自体损伤的一种现象,而是为更好地适应生存环境而主动争取的一种死亡过程。髓核细胞的过度凋亡是导致椎间盘退变的重要因素。 Wnt信号传导途径：是由配体蛋白质Wnt和膜蛋白受体结合激发的一组多下游通道的信号转导途径,通过细胞表面受体胞内段的活化过程将细胞外信号传递到细胞内。Wnt家族分泌蛋白、Frizzled家族跨膜受体蛋白Dishevelled(Dsh)、糖原合成激酶3(GSK3)、APC、Axin、β-连环蛋白及TCF/LEF家族转录调节因子等构成了经典通路,即Wnt/β-catenin信号通路。背景：课题组前期研究发现,持续负载压力可通过减少髓核细胞数量、降低髓核组织中细胞外基质的表达诱导椎间盘退变,但其作用机制尚不明确。 目的：探讨持续负载压力对髓核细胞凋亡及Wnt/β-catenin信号通路的影响。方法：采用体外兔脊柱运动节段加载模型,将脊柱运动节段分为空白对照组、压力组和观察组,压力组给予3 kg持续负载压力,观察组给予3 kg持续负载压力及Wnt通路激活剂SB216763(20 μmol/L),空白对照组不做任何处理;干预3 d后,采用苏木精-伊红染色观察髓核组织病理变化,Western blot法检测髓核组织中Caspase-3及GSK-3β蛋白表达量。结果与结论：①与空白对照组相比,压力组Caspase-3、GSK-3β蛋白表达量显著增高(P < 0.05);与压力组相比,观察组Caspase-3与GSK-3β蛋白表达量显著下降(P < 0.05);②病理组织学显示,压力组髓核细胞数量减少,细胞形态改变;观察组髓核细胞数量相对较多,细胞形态相对规整;③结果表明,持续负载压力可通过介导Wnt/β-catenin信号通路调控Caspase-3、GSK-3β的表达,促进髓核细胞凋亡。 ORCID: 0000-0002-3388-4215(尹逊路) 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

APC与XVnt／β-catenin信号转导途径

APC是Wnt信号转导通路的重要组成分子.APC蛋白可控制β-catenin在细胞内的含量,在Wnt信号转导通路中起负向调节作用.APC基因突变或蛋白异常可使Wnt信号转导通路异常激活,多种原癌基因持续转录而导致肿瘤发生.本文主要探讨APC基因失活的机制和对Wnt信号转导通路的影响.     

Wnt信号通路在成骨细胞中的作用:成骨还是破骨?

背景:研究表明,Wnt信号通路参与调节骨髓间充质干细胞向成骨细胞分化,促进成骨细胞增殖和分化,抑制成骨细胞的程序性死亡,间接影响破骨细胞的功能。目的:分析Wnt/β-连环蛋白信号通路与骨疾病的关系。方法:通过计算机检索CNKI和Elsevier数据库中2000年1月至2014年1月文献,关键词为"Wnt/β-连环蛋白、成骨细胞、骨髓间充质干细胞、骨质疏松,骨关节炎"。选择与Wnt/β-连环蛋白信号通路对成骨细胞及骨疾病影响有关的文章内容进行归纳分析。结果与结论:Wnt信号通路包括Wnt/β-连环蛋白信号通路(Wnt经典信号通路);Wnt/Ca2+信号通路;Wnt/PCP(平面细胞极性)信号通路等。Wnt信号途径是体内重要的信号调节系统之一,对成骨细胞、破骨细胞和软骨细胞的分化、增殖和程序性死亡过程中扮演重要角色。在类风湿关节炎患者体内Wnt信号途径主要通过成骨细胞发挥作用。其成骨细胞中Wnt信号途径的抑制因子上调,能够降低骨保护素/受体活化因子配体比值,促进破骨细胞分化成熟。研究Wnt通路的组分及其作用,不仅有助于骨疾病的特定治疗,而且有利于预防骨质疏松及其他关节性等疾病。     

Wnt/β-catenin信号转导途径与造血调控

Wnt基因及其激活的经典Wnt/β- catenin信号转导途径不仅参与胚胎发育,在造血干 /祖细胞 (HSC/HPC)及T和B淋巴细胞的发育、维持和自我更新中也具有重要的调控作用。     

微环境调控毛囊干细胞增殖与分化的研究进展

毛囊干细胞生存的微环境改变使毛囊干细胞的增殖、分化也发生改变。微环境对干细胞的调控是通过信号转导通路及一些重要的信号分子实现的,如整合素家族、Wnt和Notch信号转导通路及c-myc基因和β-连环蛋白等。     

细胞凋亡相关的信号通路

目前研究较多的细胞凋亡信号通路有wnt及JNK两条。Wnt信号通路有经典wnt通路,wnt/PCP通路和wnt/钙离子通路三个分支,引起细胞凋亡的机制主要有β-连环蛋白/tcf的转录调节途径,APC激活途径两种。JNK信号通路通过MKKKs-MKKs-MAPK转导。激活的JNK信号通路通过磷酸化转录因子、细胞骨架相关蛋白、酶等多种底物来调节细胞的生理过程,最终导致细胞凋亡。     

Wnt/β-catenin 信号通路在肿瘤干细胞中作用研究进展

 Wnt 信号通路是调控细胞生长、运动和分化的关键途径，在胚胎和器官发育以及维持干细胞的自我更新方面起重要作用。近年来的研究表明^[1]，Wnt/β-连环蛋白（β-catenin）信号通路的不恰当激活，参与了肿瘤的发生及其侵袭转移的过程，而且还与肿瘤干细胞（tumor stem cells，TSC）的关系密切，该通路可能通过作用于TSC而引起肿瘤产生耐受及复发，作用机制与其作用于干细胞的机制类似，从而为肿瘤的治疗提供了新的突破口。本文就 Wnt 通路中最为常见的 Wnt/β-catenin 信号通路在干细胞、肿瘤和 TSC 中作用的研究现状做一简要概述。......     

β-连环蛋白在转染p120ctn同工蛋白3A的肝癌细胞中的表达变化

目的观察β-连环蛋白在转染p120ctn同工蛋白3A的肝癌细胞中的表达变化；为通过这一途径实施肿瘤的基因治疗提供实验依据。方法对BEL-7404人肝癌细胞进行稳定转染p120ctn同工蛋白3A，然后用激光共聚焦显微镜和免疫印迹技术，检测B一连环蛋白在细胞中的表达情况，同时检测细胞黏附、细胞迁移以及增殖能力的改变。结果肝癌细胞转染p120ctn同工蛋白3A后，促进了β-连环蛋白与上皮钙黏蛋白的结合，表现为其与上皮钙黏蛋白的沉淀量增加，在细胞膜上的表达增强，在细胞核中的表达趋向减弱；细胞黏附能力增强，迁移及增殖能力下降。结论转染p120ctn同工蛋白3A，能弱化β-连环蛋白在细胞核中的表达量，削弱了BEL-7404人肝癌细胞的恶性行为，是调控β-连环蛋白癌基因表达的有效途径之一。     

降钙素对关节软骨细胞中β连环蛋白和分泌型frizzled相关蛋白1的影响

背景:研究表明降钙素具有抗骨吸收作用,对软骨有保护作用,但其具体机制尚不明确。目的:探讨降钙素是否通过Wnt/β信号通路对关节软骨细胞起保护作用。方法:分离培养雄性日本大耳白兔关节软骨细胞,随机分为对照组,白细胞介素1β组和降钙素组,后两组细胞于传代后的第2天加入白细胞介素1β(1×10-5g/L)模拟骨关节炎发生,降钙素组第4天换成含有降钙素的完全培养基。第6天采用免疫细胞化学法检测β连环蛋白的表达,以及实时荧光定量PCR法检测β连环蛋白与分泌型frizzled相关蛋白1mRNA的表达。结果与结论:降钙素组β连环蛋白和mRNA的表达显著低于白细胞介素1β组(P0.05);白细胞介素1β组β连环蛋白和mRNA的表达显著高于对照组(P0.05)。降钙素组分泌型frizzled相关蛋白1的mRNA表达显著高于白细胞介素1β组(P0.05),白细胞介素1β组分泌型frizzled相关蛋白1mRNA表达显著低于对照组(P0.05)。这些结果说明降钙素能抑制关节软骨细胞的进一步损伤,可能是通过Wnt/β连环蛋白信号通路对关节软骨细胞起保护作用。     

CTNNB1, AXIN1 and APC expression analysis of different medulloblastoma variants

OBJECTIVES:

We investigated four components of the Wnt signaling pathway in medulloblastomas. Medulloblastoma is the most common type of malignant pediatric brain tumor, and the Wnt signaling pathway has been shown to be activated in this type of tumor.

METHODS:

Sixty-one medulloblastoma cases were analyzed for β-catenin gene (CTNNB1) mutations, β-catenin protein expression via immunostaining and Wnt signaling pathway-related gene expression. All data were correlated with histological subtypes and patient clinical information.

RESULTS:

CTNNB1 sequencing analysis revealed that 11 out of 61 medulloblastomas harbored missense mutations in residues 32, 33, 34 and 37, which are located in exon 3. These mutations alter the glycogen synthase kinase-3β phosphorylation sites, which participate in β-catenin degradation. No significant differences were observed between mutation status and histological medulloblastoma type, patient age and overall or progression-free survival times. Nuclear β-catenin accumulation, which was observed in 27.9% of the cases, was not associated with the histological type, CTNNB1 mutation status or tumor cell dissemination. The relative expression levels of genes that code for proteins involved in the Wnt signaling pathway (CTNNB1, APC, AXIN1 and WNT1) were also analyzed, but no significant correlations were found. In addition, large-cell variant medulloblastomas presented lower relative CTNNB1 expression as compared to the other tumor variants.

CONCLUSIONS:

A small subset of medulloblastomas carry CTNNB1 mutations with consequent nuclear accumulation of β-catenin. The Wnt signaling pathway plays a role in classic, desmoplastic and extensive nodularity medulloblastoma variants but not in large-cell medulloblastomas.     

Wnt/β-catenin signalling pathway following rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide

The Wnt/β-catenin signaling pathway plays an important role in development, tissue homeostasis, and regeneration. Inappropriate activation of the Wnt pathway is linked to a wide range of human cancers. The purpose of this study was to characterize the Wnt/β-catenin signaling pathway as depicted by the expression of Wnt1, Frizzled-1, Wnt5a, Frizzled-5 and β-catenin during 4NQO-induced rat tongue carcinogenesis by immunohistochemistry. Male Wistar rats were distributed into three groups of 10 animals each and treated with 4NQO solution at 50 ppm through their drinking water for 4, 12, and 20 weeks. Ten animals were used as control group. No histopathological abnormalities were induced in the epithelium after 4 weeks of carcinogen exposure; however, an overexpression of Wnt5a was noticed when compared to control group (p < 0.05). The Wnt1 showed significant differences (p < 0.05) in pre-neoplastic lesions at 12 weeks following carcinogen exposure. In well-differentiated squamous cell carcinoma induced after 20 weeks of treatment with 4NQO, Wnt1 was expressed in the majority of the dysplasic cells and tumor cells. This was statistically significant (p < 0.05). No significant differences (p > 0.05) were found in expression of Frizzled-1, Frizzled-5 or β-catenin following oral carcinogenesis. Taken together, our results support the belief that expression of Wnt1 and Wnt5a is related to malignant transformation and conversion of oral mucosa.     

Induction of canonical Wnt signaling by alsterpaullone is sufficient for oral tissue fate during regeneration and embryogenesis in Nematostella vectensis

Although regeneration is widespread among metazoa, the molecular mechanisms have been studied in only a handful of taxa. Of these taxa, fewer still are amenable to studies of embryogenesis. Our understanding of the evolution of regeneration, and its relation to embryogenesis, therefore remains limited. Using β-catenin as a marker, we investigated the role of canonical Wnt signaling during both regeneration and embryogenesis in the cnidarian Nematostella vectensis. The canonical Wnt signaling pathway is known to play a conserved role in primary axis patterning in triploblasts. Induction of Wnt signaling with alsterpaullone results in ectopic oral tissue during both regeneration and embryogenesis by specifically upregulating β-catenin expression, as measured by qRTPCR. Our data indicate that canonical Wnt signaling is sufficient for oral patterning during Nematostella regeneration and embryogenesis. These data also contribute to a growing body of literature indicating a conserved role for patterning mechanisms across various developmental modes of metazoans.     

SATB1 and colorectal cancer in Wnt/β-catenin signaling: Is there a functional link?

Colorectal cancer is the third most common malignant cancer worldwide and molecular mechanisms of cancer metastasis are poorly understood. Researches suggested that the canonical Wnt/β-catenin signaling pathway plays a critical role in development and cancer. β-catenin acts as a component of the Wnt signaling in addition to being an integral component of adherens junctions. The traditional notion that β-catenin dysregulation caused by inactivating mutation of APC cannot completely elucidate the role of β-catenin in invasion and metastasis. Recently, the important roles of SATB1in T-cell development and differentiation and in promotion of breast tumor growth and metastasis were reported. The hypothesis we proposed is that SATB1 may be involved in the development and progression of colorectal cancer in a Wnt/β-catenin signaling-dependent manner.     

Wnt Signaling as a Possible Promoting Factor of Cell Differentiation in Pleomorphic Adenomas

There are well known that Wnt signaling was some roles of cell differentiation at the development tissues, especially the oral and maxillofacial regions of some developmental stages. Therefore, to determine Wnt signaling in the pleomorphic adenoma tissues, we examined. The expression of Wnt1 and β-catenin as well as the distribution of various cytoskeletal proteins CK7 and CK13 was examined in 30 cases of pleomorphic adenoma by immunohistochemistry. Wnt1 was detected in almost all tumor cells. The peripheral columnar cells in squamous metaplasia and small cuboidal cells in duct-like structures were strongly positive to Wnt1. Although β-catenin was clearly localized on the cell membrane of tumor cells, nuclear translocation was observed in small cuboidal cells and in some basaloid cells. The immunofluorescent staining pattern of Wnt1 and CK7 as well as Wnt1 and CK13 was consistent with IHC results. Thus, in pleomorphic adenoma, Wnt is involved in tumor cell differentiation of peripheral columnar cells forming solid nests and small peripheral columnar cells forming duct-like structures. Moreover, among the three currently known Wnt pathways, β-catenin is the suggested pathway working during cell differentiation. Furthermore, peripheral columnar cells in solid tumor nests and in squamous metaplasia are governed by another Wnt pathway other than β-catenin. Therefore, Wnt signaling through β-catenin pathway may be involved in the ''mixed'' differentiation characteristic of pleomorphic adenoma although another pathway may also be possibly working in other parts of the tumor tissue.     

β-catenin的生物学功能与调控机制

β-连环蛋白(β-catenin)是一种胞内糖蛋白,具有双重功能.一是作为附着连接的组成部分,与钙黏蛋白结合形成复合体参与细胞间连接;二是作为信号分子,是Wnt信号途径的重要环节,在胚胎发育和肿瘤发生中起重要作用.β-catenin选择何种途径发挥作用,与不同配体竞争性结合密切相关.目前已经证实β-catenin Y142位点酪氨酸磷酸化是决定β-catenin功能的关键调控点,而E-cadherin、Lef1、APC和α-catenin 均参与β-catenin活性的调节,对细胞的命运有着重要影响.