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Wnt/b-catenin signaling plays an ever-expanding role in stem cell self-renewal,tumorigenesis and cancer chemoresistance

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Genes & Diseases 2016年第1期3卷 11-40页

作者： Maryam K.Mohammed Connie Shao Jing Wang Qiang Wei Xin Wang Zachary Collier Shengli Tang Hao Liu Fugui Zhang Jiayi Huang Dan Guo Minpeng Lu Feng Liu Jianxiang Liu Chao Ma Lewis L.Shi Aravind Athiviraham Tong-Chuan He Michael J.Lee The University of Chicago Pritzker School of Medicine ChicagoIL 60637USA Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Ministry of Education Key Laboratory of Diagnostic Medicine and the Affiliated Hospitals of Chongqing Medical UniversityChongqing 400016China Department of Surgery West China Hospital of Sichuan UniversityChengdu 610041China Departments of General Surgery and Neurosurgerythe Affiliated Zhongnan Hospital of Wuhan UniversityWuhan 430071China Department of Orthopaedic Surgery Union Hospital of Tongji Medical CollegeHuazhong University of Science&TechnologyWuhan 430022China

Wnt signaling transduces evolutionarily conserved pathways which play important roles in initiating and regulating a diverse range of cellular activities,including cell proliferation,calcium homeostasis,and cell *** role of Wnt signaling in controlling cell proliferation and stem cell self-renewal is primarily carried out through the canonical pathway,which is the best-characterized the multiple Wnt signaling *** past 10 years has seen a rapid expansion in our understanding of the complexity of this pathway,as many new components of Wnt signaling have been identified and linked to signaling regulation,stem cell functions,and adult tissue ***,a substantial body of evidence links Wnt signaling to tumorigenesis of cancer types and implicates it in the development of cancer drug ***,a better understanding of the mechanisms by which dysregulation of Wnt signaling precedes the development and progression of human cancer may hasten the development of pathway inhibitors to augment current *** review summarizes and synthesizes our current knowledge of the canonical Wnt pathway in development and *** begin with an overview of the components of the canonical Wnt signaling pathway and delve into the role this pathway has been shown to play in stemness,tumorigenesis,and cancer drug ***,we hope to present an organized collection of evidence implicating Wnt signaling in tumorigenesis and chemoresistance to facilitate the pursuit of Wnt pathway modulators that may improve outcomes of cancers in which Wnt signaling contributes to aggressive disease and/or treatment resistance.

关键词： Cancer drug resistance Cancer stem cells Canonical Wnt b-catenin Wnt

Crosstalk of the Wnt/b-catenin pathway with other pathways in cancer cells

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Genes & Diseases 2016年第1期3卷 41-47页

作者： Saint-Aaron L.Morris Suyun Huang Department of Neurosurgery The University of Texas MD Anderson Cancer Center1515 Holcombe BoulevardHoustonTX 77030USA Program in Cancer biology The University of Texas Graduate School of Biomedical Sciences6767 Bertner AvenueMitchell Building BSRB S3.8344HoustonTX 77030USA

Many cancers have similar aberrations in various signaling cascades with crucial roles in cellular proliferation,differentiation,and *** of signal cascades that play integral roles during early cellular development is well known to be a central feature of many *** such signaling cascade is the Wnt/b-catenin pathway,which has a profound effect on stem cell proliferation,migration,and *** pathway is dysregulated in numerous cell types,underscoring its global oncogenetic *** review highlights regulators and downstream effectors of this receptor cascade and addresses the increasingly apparent crosstalk of Wnt with other tumorigenic signaling *** understanding of the genetic and epigenetic changes unique to these malignancies increases,identifying the regulatory mechanisms unique to the Wnt/b-catenin pathway and similarly aberrant receptor pathways will be imperative.

关键词： b-catenin Cell signaling Glioma stem cell Tumorigenicity Wnt

Current understanding and dispute on the function of the Wnt signaling pathway effector TCF7L2 in hepatic gluconeogenesis

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Genes & Diseases 2016年第1期3卷 48-55页

作者： Tianru Jin Department of Medicine University of TorontoTorontoCanada

Approximately 10 years ago,the Wnt signaling pathway effector TCF7L2(ZTCF-4)was recognized as a type 2 diabetes(T2D)risk gene through a genome wide association study(GWAS).As the correlation between TCF7L2 polymorphisms and T2D susceptibility has been reproducibly observed by numerous follow-up investigations among different ethnic groups,great efforts have been made to explore the function of TCF7L2 in metabolic organs including the pancreas,liver and adipose *** these explorations have enriched our general knowledge on the Wnt signaling cascade in metabolic homeostasis,studies conducted to date have also generated controversial *** I will provide a brief review on the Wnt signaling pathway as well as the milestone GWAS discovery and the follow-up studies.I will then discuss the two different opinions on the correlation between TCF7L2 variants and T2D risk,a gain-of-function event versus a loss-of-function *** will be followed by summarizing the relevant investigations on the metabolic function of hepatic TCF7L2 and presenting our view on the discrepancy and perspectives.

关键词： b-catenin Gluconeogenesis Insulin TCF7L2 Transgenic mice Type 2 diabetes Wnt

Emerging signals regulating liver tumor initiating cells

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Liver Research 2018年第2期2卷 73-80页

作者： Jingyu Chen Chien-Yu Chen Christopher Nguyen Lulu Chen Kangmin Lee bangyan L.Stiles Department of Pharmacology and Pharmaceutical Sciences School of PharmacyUniversity of Southern CaliforniaLos AngelesCAUSA Department of Pathology Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA

Tumor initiating cells(TICs)have been identified as cells that account for tumor *** studies demonstrated that genes controlling stem cell biology play key roles in maintaining TICs and promote their development into *** this review,we summarize findings from human and animal studies that indicate the presence of TICs during liver cancer *** identified for liver development and regeneration are used to identify liver cancer *** of these markers is often upregulated in human hepatocellular carcinoma(HCC)*** flow cytometry analysis and lineage tracing approaches,the presence of TICs is *** of TIC markers and the presence of TICs are also observed in genetically modified animals that target genes that are frequently altered in human *** presence of these TICs represents a major challenge for therapeutic devel*** signals that can regulate the fate,transformation and growth of liver TICs is an emerging need in liver ***-determining region Y-box 9(SOX9)has recently become an important marker for liver ***,we summarize the role of SOX9 in TICs and its potential interaction with other *** includes the Notch-Numb signal that controls asymmetrical-symmetrical cell division,Wnt-b-catenin signal that maintains cell fate and transforming growth factor(TGF)-b signal that acts as upstream inducers.

关键词： Liver cancer Hepatocellular carcinoma(HCC) Tumor initiating cells(TICs) Sex-determining region Y-box 9(SOX9) b-catenin Notch Numb Transforming growth factor(TGF)-b

辛伐他汀促大鼠bMSCs成骨分化作用机制的研究

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现代预防医学 2010年第17期37卷 3324-3326页

作者：吕志伟常玉坤王成刚华北煤炭医学院解剖学教研室华北煤炭医学院附属人民医院外科华北煤炭医学院临床医学系

[目的]研究辛伐他汀(simvastatin,SIM)促进大鼠骨髓基质干细胞(bone marrow stromal cells,bMSCs)向成骨细胞分化的作用机制。[方法]取4周雌性SD大鼠双侧股骨、胫骨骨髓细胞进行体外成骨诱导培养,并于第一次传代后(d8)加入浓度为10-7mol... 详细信息

[目的]研究辛伐他汀(simvastatin,SIM)促进大鼠骨髓基质干细胞(bone marrow stromal cells,bMSCs)向成骨细胞分化的作用机制。[方法]取4周雌性SD大鼠双侧股骨、胫骨骨髓细胞进行体外成骨诱导培养,并于第一次传代后(d8)加入浓度为10-7mol/LSIM(给药组,SIM组)或等量溶剂培养(对照组,N组),d16行碱性磷酸酶(ALP)染色,d28行vonKossa染色观察细胞外基质矿化,并采用realtime RT-PCR法于上述两个时间点检测b-catenin、bMP-2、Smad1、ALP、OCN、mRNA的表达。[结果]①辛伐他汀可促进成骨诱导分化大鼠bMSCs的ALP表达及细胞外基质的矿化能力。②mRNA表达水平:d16SIM组ALP的表达显著高于N组;d28SIM组bMP-2、Smad1、OCN表达水平均明显高于N组,b-catenin的表达显著低于N组(P﹤0.05)。[结论]辛伐他汀可促进大鼠bMSCs向成骨细胞分化,其作用机制可能与调节TGFβ/bMP、WNT信号途径相关基因的表达水平有关。

关键词：辛伐他汀骨髓基质干细胞成骨分化 bMP-2 b-catenin

穿心莲内酯抑制黑色素合成的效果及其机制研究

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穿心莲内酯抑制黑色素合成的效果及其机制研究

作者：朱萍亚华东师范大学

学位级别：硕士

随着环境污染的加深,导致大气中臭氧空洞的形成与扩大,使得更多的紫外线穿透云层抵达地面,使人体皮肤等部位接收到更多的紫外线。而紫外线包括UVA和UVb可以促使人皮肤中黑色素细胞合成黑色素的能力加深,导致皮肤色素沉积失常,造成晒斑,... 详细信息

随着环境污染的加深,导致大气中臭氧空洞的形成与扩大,使得更多的紫外线穿透云层抵达地面,使人体皮肤等部位接收到更多的紫外线。而紫外线包括UVA和UVb可以促使人皮肤中黑色素细胞合成黑色素的能力加深,导致皮肤色素沉积失常,造成晒斑,影响面容状况,给患者带来一定的心理和精神压力。而现存的美白剂,如曲酸和熊果苷皆存在着不足之处,因而筛选出可以抑制黑色素合成的天然美白产品具有巨大的应用价值和经济价值。在本文中,我们以小鼠黑色素瘤细胞b16F10为细胞模型,初步筛选出可以抑制黑色素含量的天然植物单体——穿心莲内酯。然后检测了酪氨酸酶活性、酪氨酸酶家族与其上游因子小眼相关转录因子的转录和蛋白表达以及黑色素合成过程中的相关信号分子蛋白表达量来研究植物单体抑制黑色素含量的机制,发现穿心莲内酯可以可以通过抑制Akt的磷酸化抑制GSK3β的磷酸化,从而抑制β-catenin的入核,下调小眼相关转录因子的转录,最终降低了酪氨酸酶的活性和黑色素的生成。并在紫外线UVb照射诱导色素沉积的棕黄色豚鼠和人黑色素细胞(Human Epidermis Melanocyte, HEM)上验证了该植物单体可以抑制黑色素合成的效果。本论文具体可分为以下四个部分：第一部分是“抑制黑色素合成的天然药物单体的筛选”。以b16F10细胞为黑色素抑制因子的初筛模型,选择曲酸作为美白剂的阳性药物,采用无酚红的含有待测药物的DMEM培养基培养细胞,待黑色素从细胞中分泌出来抵达上清液时,通过检测其在490nmm下的吸光值,从而筛选出可以抑制上清液OD值的植物单体,并查阅文献,找到一种文献中极少有报导的植物单体——穿心莲内酯。第二部分是“穿心莲内酯抑制体外细胞黑色素合成的研究”。首先检测了穿心莲内酯对b16F10细胞和HEM细胞活性的影响,然后再检测其对两种细胞中黑色素含量的影响,结果表明穿心莲内酯可以在不影响细胞增殖的前提下,有效抑制b16F10细胞和HEM细胞的黑色素含量,且呈剂量依赖性。然后检测了穿心莲内酯对b16F10和HEM两种细胞胞内酪氨酸酶活性和两种分别来自于蘑菇与小鼠的酪氨酸酶活性的影响,表明穿心莲内酯会影响胞内酪氧酸酶活性而不改变酪氨酸酶的催化活性结构。再通过实时荧光定量Q-PCR和蛋白免疫印迹实验检测酪氨酸酶家族和小眼相关转录因子的转录水平和蛋白表达含量,结果说明穿心莲内酯可以有效抑制酪氨酸酶家族和小眼相关转录因子的基因转录和蛋白表达。因此,穿心莲内酯可以通过抑制小眼相关转录因子的基因转录降低小眼相关转录因子的蛋白表达,从而抑制其靶基因酪氨酸酶家族的基因转录和蛋白表达,最终降低酪氨酸酶活性和黑色素含量。第三部分是“穿心莲内酯抑制动物皮肤黑色素合成的研究”。采用婴儿理发器和电动剃须刀,使棕黄色豚鼠背部出现四块2cm*2cm大小的裸露区域。然后使豚鼠一次性照射剂量为2J/cm2的UVb,再涂抹膏霜,每天两次。待四块区域的皮肤颜色出现差异时,剃净背部毛发。然后进行拍照,再将皮肤制成皮肤切片后进行免疫组织化学实验。结果显示5% 穿心莲内酯可以有效降低棕黄色豚鼠皮肤中经紫外线照射诱导产生的色素沉着、黑色素颗粒含量和酪氨酸酶蛋白含量以及酪氨酸酶阳性细胞数目,且抑制效果与5%曲酸相差不大。因此,穿心莲内酯可以通过抑制酪氨酸酶蛋白含量,降低酪氨酸酶阳性细胞数目,抑制黑色素细胞分化,从而抑制黑色素的合成,最终抑制棕黄色豚鼠皮肤中经紫外线照射诱导的皮肤色素沉着。第四部分是“穿心莲内酯抑制黑色素合成的分子机制探讨”。通过蛋白免疫印迹实验,发现b16F10细胞经穿心莲内酯处理后,其胞内β-catenin蛋白含量、glycogen synthase kinase 3β (GSK3β)和Akt磷酸化水平显著下降,同时β-catenin的入核量明显降低。再通过MG132和放线菌酮实验,发现穿心莲内酯加快了β-catenin经蛋白酶体的降解过程。而GSK3β抑制剂可以抑制由穿心莲内酯导致的β-catenin的含量、酪氨酸酶的活性和黑色素的含量的减少。Akt激活剂可以抑制由穿心莲内酯导致的p-Akt, GSK3β, β-catenin含量的下降。因此,穿心莲内酯可以通过调控Akt磷酸化来减少GSK3β的失活,从而加速β-catenin降解,抑制β-catenin的入核,最终抑制了小眼相关转录因子的基因转录。

关键词：黑色素酪氨酸酶小眼相关转录因子 b-catenin p-Akt

β-catenin参与肿瘤干细胞形成和增殖转移的研究进展

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现代肿瘤医学 2014年第4期22卷 941-943页

作者：杨西胜汪建林李小磊李海民第四军医大学西京医院肝胆外科陕西西安710032

catenin是一类具有相似结构的胞浆内糖蛋白家族,根据分子量不同分为α、β、γ及p120ctn四个亚型,最初是因其与跨膜黏附分子E-cad的胞质段连接而被发现和命名。β-catenin(β-连环素)是一种由位于染色体3p21-22的CTNNb1基因编码的具有... 详细信息

catenin是一类具有相似结构的胞浆内糖蛋白家族,根据分子量不同分为α、β、γ及p120ctn四个亚型,最初是因其与跨膜黏附分子E-cad的胞质段连接而被发现和命名。β-catenin(β-连环素)是一种由位于染色体3p21-22的CTNNb1基因编码的具有介导细胞间黏附及信号转导等多重功能的重要分子,其通过与多种蛋白质结合调控细胞的增殖和分化,在胚胎发育和肿瘤发生中发挥关键作用。近年来干细胞是肿瘤研究领域的热点问题,作为Wnt信号转导通路枢纽分子β-catenin的异常表达与肿瘤的发生、发展有关,因此β-catenin在肿瘤干细胞中的作用也引起科研人员的密切关注。

关键词： IWnt b-catenin 肿瘤干细胞细胞增殖

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非小细胞肺癌中过表达RNF146对Axin和β-catenin表达和定位的影响

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现代肿瘤医学 2014年第4期22卷 737-741页

作者：高英徐慧慧李锐王睿惠林萍邱雪杉王恩华中国医科大学附属第四医院病理科辽宁沈阳110032 中国医科大学附属第四医院中心实验室辽宁沈阳110032 中国医科大学基础医学院病理教研室及附属第一医院病理科辽宁沈阳110001

目的:观察E3泛素连接酶RNF146表达对Axin和β-catenin蛋白表达的影响,探讨RNF146与Wnt/β-catenin信号通路在非小细胞肺癌(NSCLC)发生发展中的作用。方法:应用免疫组织化学EnVision法检测133例NSCLC患者肺癌中RNF146、Axin和β-catenin... 详细信息

目的:观察E3泛素连接酶RNF146表达对Axin和β-catenin蛋白表达的影响,探讨RNF146与Wnt/β-catenin信号通路在非小细胞肺癌(NSCLC)发生发展中的作用。方法:应用免疫组织化学EnVision法检测133例NSCLC患者肺癌中RNF146、Axin和β-catenin的表达。构建RNF146过表达质粒,应用逆转录聚合酶链反应(RT-PCR)、Western blot和细胞免疫荧光方法研究RNF146在肺癌细胞株A549和LTE中过表达对Axin和β-catenin表达及定位的影响。结果:NSCLC患者肺癌组织中RNF146高表达72例(54.1%)中49例(68.1%)显示Axin表达减弱或缺失,19例(26.4%)出现β-catenin细胞核阳性表达;RNF146低表达61例(45.9%)中只有26例(42.6%)显示Axin表达减弱或缺失,7(11.5%)例出现β-catenin细胞核阳性。RNF146与Axin的表达呈明显的负相关(P=0.003),与β-catenin的细胞核表达呈正相关(P=0.047)。肺癌细胞系中过表达RNF146能够下调Axin蛋白的表达,诱导β-catenin蛋白表达和核内分布,但对Axin和β-catenin mRNA水平没有影响。结论:RNF146可能通过Wnt/β-catenin通路参与肺癌的发生发展。

关键词：非小细胞肺癌 E3泛素连接酶 RNF146 Axin b-catenin

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