Article(id=1207433497950655396, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1207433493215289544, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2022.08.0831, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1624723200000, receivedDateStr=2021-06-27, revisedDate=null, revisedDateStr=null, acceptedDate=1628524800000, acceptedDateStr=2021-08-10, onlineDate=1765804178941, onlineDateStr=2025-12-15, pubDate=1661616000000, pubDateStr=2022-08-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1765804178941, onlineIssueDateStr=2025-12-15, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1765804178941, creator=13701087609, updateTime=1765804178941, updator=13701087609, issue=Issue{id=1207433493215289544, tenantId=1146029695717560320, journalId=1189873630562394117, year='2022', volume='47', issue='8', pageStart='745', pageEnd='850', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1765804177811, creator=13701087609, updateTime=1765804292764, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1207433975413444883, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1207433493215289544, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1207433975413444884, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1207433493215289544, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=831, endPage=837, ext={EN=ArticleExt(id=1207433498286199734, articleId=1207433497950655396, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Research progress of Wnt/β-catenin signaling pathway in cancer stem cells, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

The incidence and mortality of malignant tumors are gradually increasing all the world, and the existing diagnosis and treatment methods still can not effectively block the occurrence and development of tumors. Some studies have found that cancer stem cells (CSCs) are the cells of tumor origin, and closely related to the occurrence, development and metastasis of tumors.Early detection and intervention with effective treatment of CSCs are expected to prevent the occurrence and development of tumors. Many studies have shown that the activation of Wnt/β-catenin signaling pathway is an important link in the initiation of CSCs and the formation of tumors. Therefore, by regulating the key upstream and downstream factors of the Wnt/β-catenin pathway in CSCs, thereby regulating the activity of the Wnt/β-catenin signaling pathway, controlling tumor growth and metastasis,can provide new targets and directions for the treatment and prevention of malignant tumors. The key role of Wnt/β-catenin signal pathway in CSCs, and the related mechanisms of the important factors of the pathway in regulating the tumor growth, development and metastasis of CSCs in different organs are reviewed in present paper.

, correspAuthors=Hui Zhao, authorNote=null, correspAuthorsNote=
*E-mail:
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全球恶性肿瘤的发病率及死亡率呈逐渐升高趋势,现有的诊疗手段仍不能有效阻断肿瘤的发生和发展。肿瘤干细胞(CSCs)是肿瘤的起源细胞,与肿瘤的发生、发展及转移密切相关。若早期发现CSCs并有效的治疗方式进行干预,有望阻止肿瘤的发生与发展。Wnt/β-catenin信号通路的激活是CSCs启动及肿瘤形成的重要环节,通过调节CSCs中Wnt/β-catenin信号通路的上下游关键因子来调控该通路的活性,控制肿瘤的生长及转移,可为恶性肿瘤的治疗与预防提供新的靶点和方向。本文对Wnt/β-catenin信号通路在CSCs中的作用,以及该通路中关键因子调控CSCs在不同脏器肿瘤发生、发展及转移中的相关机制进行综述。

, correspAuthors=赵辉, authorNote=null, correspAuthorsNote=
赵辉,E-mail:
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田宇佳,硕士研究生,主要从事肺癌基础与临床方面的研究

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田宇佳,硕士研究生,主要从事肺癌基础与临床方面的研究

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Wnt/β-catenin信号通路在肿瘤干细胞中的作用研究进展
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田宇佳 1, 2 , 魏铭 1 , 赵辉 3, *
解放军医学杂志 | 综述 2022,47(8): 831-837
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解放军医学杂志 | 综述 2022, 47(8): 831-837
Wnt/β-catenin信号通路在肿瘤干细胞中的作用研究进展
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田宇佳1, 2, 魏铭1, 赵辉3, *
作者信息
  • 1大连医科大学附属第二医院研究生院,辽宁大连 116027
  • 2大连市第三人民医院呼吸与危重症医学科,辽宁大连 116091
  • 3大连医科大学附属第二医院健康管理中心,辽宁大连 116027
  • 田宇佳,硕士研究生,主要从事肺癌基础与临床方面的研究

通讯作者:

赵辉,E-mail:
Research progress of Wnt/β-catenin signaling pathway in cancer stem cells
Yu-Jia Tian1, 2, Ming Wei1, Hui Zhao3, *
Affiliations
  • 1Graduate School, the Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, China
  • 2Department of Respiratory and Critical Care Medicine, Dalian Third People's Hospital, Dalian, Liaoning 116091, China
  • 3Health Management Center, the Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, China
出版时间: 2022-08-28 doi: 10.11855/j.issn.0577-7402.2022.08.0831
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全球恶性肿瘤的发病率及死亡率呈逐渐升高趋势,现有的诊疗手段仍不能有效阻断肿瘤的发生和发展。肿瘤干细胞(CSCs)是肿瘤的起源细胞,与肿瘤的发生、发展及转移密切相关。若早期发现CSCs并有效的治疗方式进行干预,有望阻止肿瘤的发生与发展。Wnt/β-catenin信号通路的激活是CSCs启动及肿瘤形成的重要环节,通过调节CSCs中Wnt/β-catenin信号通路的上下游关键因子来调控该通路的活性,控制肿瘤的生长及转移,可为恶性肿瘤的治疗与预防提供新的靶点和方向。本文对Wnt/β-catenin信号通路在CSCs中的作用,以及该通路中关键因子调控CSCs在不同脏器肿瘤发生、发展及转移中的相关机制进行综述。

恶性肿瘤  /  肿瘤干细胞  /  Wnt/β-catenin信号通路  /  治疗靶点

The incidence and mortality of malignant tumors are gradually increasing all the world, and the existing diagnosis and treatment methods still can not effectively block the occurrence and development of tumors. Some studies have found that cancer stem cells (CSCs) are the cells of tumor origin, and closely related to the occurrence, development and metastasis of tumors.Early detection and intervention with effective treatment of CSCs are expected to prevent the occurrence and development of tumors. Many studies have shown that the activation of Wnt/β-catenin signaling pathway is an important link in the initiation of CSCs and the formation of tumors. Therefore, by regulating the key upstream and downstream factors of the Wnt/β-catenin pathway in CSCs, thereby regulating the activity of the Wnt/β-catenin signaling pathway, controlling tumor growth and metastasis,can provide new targets and directions for the treatment and prevention of malignant tumors. The key role of Wnt/β-catenin signal pathway in CSCs, and the related mechanisms of the important factors of the pathway in regulating the tumor growth, development and metastasis of CSCs in different organs are reviewed in present paper.

malignant tumor  /  cancer stem cells  /  Wnt/β-catenin signaling pathway  /  therapeutic target
田宇佳, 魏铭, 赵辉. Wnt/β-catenin信号通路在肿瘤干细胞中的作用研究进展. 解放军医学杂志, 2022 , 47 (8) : 831 -837 . DOI: 10.11855/j.issn.0577-7402.2022.08.0831
Yu-Jia Tian, Ming Wei, Hui Zhao. Research progress of Wnt/β-catenin signaling pathway in cancer stem cells[J]. Medical Journal of Chinese People’s Liberation Army, 2022 , 47 (8) : 831 -837 . DOI: 10.11855/j.issn.0577-7402.2022.08.0831
《2020年全球癌症报告》指出,2020年全球新发恶性肿瘤约1929万例,其中乳腺癌、肺癌居前两位,且呈逐年增长趋势;全球恶性肿瘤死亡近996万例,成为全球第二大死亡原因,其中肺癌、乳腺癌、大肠癌等恶性肿瘤的死亡率呈升高趋势[1]。目前,恶性肿瘤的检查和诊断手段已取得很大进步,提高了肿瘤的诊断率,新的治疗手段的出现也为肿瘤治疗提供了更多的方案。然而,恶性肿瘤生长迅速,确诊时往往已出现远处转移,且针对已经发生靶器官转移的晚期肿瘤患者治疗手段有限,疗效不理想[2]。因此,研究肿瘤发生发展的机制对于肿瘤的诊断、治疗具有重要的临床意义。对肿瘤干细胞(cancer stem cells,CSCs)深入研究发现,CSCs与肿瘤的形成、侵袭和复发密切相关[3],而Wnt/β-catenin信号通路在CSCs中发挥着关键作用[4]。因此,了解和掌握Wnt/β-catenin信号通路在不同CSCs中的作用,有可能为恶性肿瘤的治疗和预防提供新的靶点和研究方向。
在肿瘤组织中,少数肿瘤细胞由于多基因突变而停止在某个分化阶段无限增殖,具有干细胞的特性,被称为CSCs。肿瘤干细胞学说认为CSCs具有以下几个主要特点:一是自我更新、无限增殖和多向分化的能力,可启动肿瘤发生,是肿瘤生长的根源[5];二是较强的促血管生成能力和致瘤性,可维持肿瘤营养供给并促进其生长[6-7];三是对放疗和化疗药物有较强的抵抗力,这可能是肿瘤耐药、侵袭、复发的根本原因[8]。目前,在造血系统肿瘤[9]、乳腺癌[10]、肠癌[11]、脑胶质瘤[12]等恶性肿瘤组织中均证实了CSCs的存在。CSCs不仅与肿瘤的形成和进展有关,也与肿瘤的复发和耐药密切相关。在肿瘤治疗过程中,应用传统方法完全杀灭CSCs十分困难,尤其是已经转移到血液或靶器官的CSCs,而这部分CSCs也是引起肿瘤复发的关键因素[13]。因此,只有杀灭CSCs才是真正意义上的根治肿瘤。
CSCs的表面一般存在有助于区分其与其他肿瘤细胞的标志物,如ALDH1、CD133、CD44和SOX2等,这些标志物在不同组织和肿瘤中的表达水平并不完全相同[14]。此外,CSCs可通过多种信号通路如Wnt/β-catenin、Notch、JAK/STAT、Hippo-YAP/TAZ等发挥干细胞样特性,其中Wnt/β-catenin信号通路发挥着重要作用[4]
在Wnt信号通路中,Wnt配体与膜蛋白受体结合后可引起一系列信号因子的改变。Wnt/β-catenin信号通路作为经典的Wnt信号通路发挥着重要作用,当没有Wnt配体激活该通路时,β-catenin聚集在细胞质内,无法向核内易位,迅速被糖原合成酶激酶3β(glycogen synthase kinase 3β,GSK3β)、酪蛋白激酶1(casein kinase 1,CK1)磷酸化并隔离在破坏复合体(由APC-Axin-GSK3β-CK1组成)中,导致相关的蛋白酶体降解;当有Wnt配体存在时,Wnt配体结合细胞膜上的卷曲同源物和肺耐药蛋白5/6(lung resistance related protein 5/6,LRP5/6)受体共表达,引起散乱蛋白聚集,使该通路呈激活状态,细胞质内的β-catenin不能被GSK3β磷酸化,故大量积累并向细胞核内易位,与T细胞特异性因子(TCF)/淋巴样增强因子(LEF)或共活化因子(如Pygo和Bcl-9)互动,调节Wnt信号通路下游靶基因(如c-mycAxin2DKK1等)的表达,最终发挥相应的功能[15]。最新研究发现,Wnt/β-catenin信号通路在调控CSCs的自我更新、增殖及肿瘤形成、侵袭、转移和耐药方面起着至关重要的作用[16]
肠道肿瘤发生发展的主要原因是Wnt/β-catenin信号通路的过度激活[17]。APC-Axin-GSK3β-β-catenin复合体中任一基因突变或缺失都可激活此通路,导致CCSC过度更新、增殖和转移,有利于肿瘤形成[11]。富亮氨酸重复序列G蛋白偶联受体5(leucine-rich repeat-containing G protein-coupled receptor 5,LGR5)是一种新鉴定的CCSC表面标志物,也是Wnt/β-catenin信号通路的关键分子。LGR5在肠癌细胞中表达增加,当其缺失时,β-catenin的核内易位减少,同时c-myc和Cyclin D转录水平下降,诱导CCSC凋亡并使其生长受到抑制[18]。此外,多种重要因子也可通过Wnt/β-catenin信号通路调控CCSC的干性特征,如RNA结合蛋白3(RNA binding motif containing protein 3,RBM3)在HCT 116和DLD-1肠癌细胞系中过表达,导致侧群细胞占比增加,细胞球体数量增多,干细胞标志物(DCLK1、LGR5和CD44)表达增加,提示RBM3可促进CCSC的自我更新。RBM3过表达可增高核内β-catenin水平和TCF/LEF的转录活性,还可使GSK3β失活,导致β-catenin磷酸化水平降低,从而维持CCSC的增殖能力[19]。Zeste同系物2(Zeste homologue 2,EZH2)可通过激活Wnt/β-catenin信号通路使细胞周期停滞在G1/S期,从而维持CCSC的增殖能力[20]。环境改变也可通过Wnt/β-catenin信号通路影响CCSC的干性特征,如缺氧使CCSC表型(c-myc、SOX2和Oct4)和编码DNA结合蛋白的抑制因子2(inhibitor of DNA-binding 2,Id2)表达增加,在信号转导后β-catenin的稳定性增加,Wnt/β-catenin信号分子(Wnt1、TCF4和Cyclin D)表达增加,提示缺氧可通过激活Wnt/β-catenin信号通路增强体内和体外CCSC的增殖克隆能力。相反,Wnt/β-catenin信号通路抑制剂可抑制缺氧诱导的CD44+CCSC球体的形成,降低Id2的表达水平[21],而Id2水平升高可减缓小鼠移植瘤的生长速度。由此可见,Wnt/β-catenin信号通路和Id2共同介导了缺氧所致的CCSC增殖和转移[21]
MicroRNAs(miRNAs)可能是CCSC特性的调节器,不仅调控其自我更新和增殖能力,还可维持其侵袭和转移能力[22-23]。在肠癌中已经发现多种miRNAs通过Wnt/β-catenin信号通路调控CCSC的功能。miR-21、miR-93、miR-203、miR-215、miR-497可调控CCSC的生长和生存信号,从而调节恶性肿瘤的治疗敏感性[24]。在HCT 116和SW480细胞系中加入miR-3120-5p,细胞中Oct4、SOX2和Nanog的表达增加,肿瘤细胞的球体形成能力增强,表明miR-3120-5p促进了细胞的自我更新和克隆形成。同时,负调控因子Axin2的表达水平下降,核内β-catenin增多,表明miR-3120-5p可通过Wnt/β-catenin信号通路促进细胞的自我更新和增殖[25]。选择性抑制Axin2的靶点,可导致Wnt信号通路下游信号转录反应及时终止。高表达miR-103/107可通过靶向抑制Axin2、上调β-catenin而延长Wnt/β-catenin信号的持续时间。Wnt/β-catenin信号通路激活可增加CCSC标志物(CD44+)的表达和侧群细胞的数量,也可增加肿瘤球体的数量和体积,使其致瘤能力增强100倍[26]。miR-103/107-Axin2轴参与了化疗耐药和肿瘤复发。在裸鼠皮下植入携带荧光素酶的HCT 116衍生物,待原发肿瘤长至50 mm3时手术切除肿瘤,8周后应用活体成像系统监测原发部位或远处肿瘤的复发情况,结果显示对照组小鼠肿瘤未复发,但注射miR-103/107过表达细胞的小鼠出现肿瘤复发,提示miR-103/107-Axin2轴可能为治疗侵袭性大肠癌的潜在靶点[26]。此外,miR-199a/b通过下调CCSC内GSK3β的表达和上调β-catenin而激活Wnt/β-catenin-ABCG2途径,促进CCSC的耐药与侵袭[27]。菱形结构域蛋白1(rhomboid domain containing 1,RHBDD1)在肠癌中高表达,可促进淋巴结转移及远处转移,其机制为过表达的RHBDD1通过降低β-catenin在细胞质内的磷酸化水平,上调Wnt信号通路靶基因ZEB1的表达,从而促进结直肠癌转移[28]。RHBDD1可维持干细胞样表型并促进结直肠癌发生上皮-间质转化(epithelial-mesenchymal transition,EMT)[28]。KDM3家族组蛋白去甲基化酶(KDM3 family histone demethylases)是一种表观遗传因子,对CCSC的致瘤潜能、存活能力和转移潜能具有重要作用。KDM3可募集组蛋白甲基转移酶MLL1促进H3K4甲基化,从而上调Wnt靶基因(Axin2DKK1c-myc)的表达[29]。因此,上下游靶点失控导致了Wnt/β-catenin信号通路的激活,引起CCSC在远处定植后发生无限增殖、自我更新,最终形成肿瘤。靶向阻断该通路的信号转导抑制CCSC的干性特征,可抑制肠癌的发生、发展、转移和治疗耐药性。
Wnt/β-catenin信号通路参与调控LCSC的增殖、克隆形成、转移和耐药[30],这与β-catenin的核内积聚密切相关。β-catenin可通过上调LCSC标志物Oct4的表达,增强细胞的增殖、克隆、迁移和耐药能力。应用伊曲康唑诱导A549细胞株后,β-catenin和CD133表达下调,肺癌细胞的干细胞特性相应下降[31]。Wnt/β-catenin信号通路下游分子CD44在肺癌中过度表达,过表达的CD44可促进β-catenin向核内易位,激活Wnt/β-catenin-FOXM1-Twist信号转导通路,引起CD133+、CD44+肺腺癌干细胞发生侵袭和转移[32]。Roy等[33]发现,使用1,2,3,4-四氢异喹啉(THIQ)抑制CD44可调控Wnt/β-catenin信号蛋白的表达,而沉默β-catenin可降低CD44的表达,表明CD44与β-catenin之间存在蛋白-蛋白相互作用。抑制CD44可使顺铂耐药的CSCs对顺铂趋化,从而改善肿瘤患者的预后。Wnt/β-catenin通路激活后,下游因子FOXM1诱导CD133+、CD44+ LCSC发生EMT,导致癌细胞侵袭和扩散能力明显增强[32]。CD44作为LCSC的标志物,可激活Wnt/β-catenin信号通路,上调Nanog和Oct3/4的表达,增强肺癌细胞的自我更新能力和耐辐射性[32]。Liu等[34]发现,沉默β-catenin可抑制Oct4、Nanog介导的非小细胞肺癌(non-small cell lung cancer,NSCLC)耐药性和EMT过程。Wnt/β-catenin信号通路是治疗具有CSCs样特性和EMT表型的NSCLC进展和转移的潜在靶点。Wnt/β-catenin信号通路过度激活可启动肿瘤血管生成,这与肺癌的发生和发展关系密切。MORC家族CW型锌指蛋白2(MORC2)是一种高度保守的蛋白,与多种恶性肿瘤的形成、生长有关。研究发现,MORC2在肺癌A549细胞株中过度表达,致使β-catenin核内易位增多,同时血管内皮生长因子(vascular endothelial growth factor,VEGF)、基质金属蛋白酶(matrix metalloproteinase,MMP)-7、MMP-9、MMP-2表达水平升高,促进肿瘤血管生成,导致肿瘤扩散和生长[35]。MORC也可增加LCSC标志物ALDH1的表达,维持LCSC的干性特征。丝氨酸-精氨酸蛋白激酶1(serine-arginine protein kinase 1,SRPK1)在NSCLC中过度表达,使肺癌A549和Calu3细胞系中β-catenin核内易位和TCF/LEF转录活性增强,导致靶基因CD44CCND1c-mycc-jun表达增加,促进血管生成,从而导致肿瘤的发生[36]。相反,抑制SRPK1可降低β-catenin核内易位和靶基因的转录活性,从而抑制LCSC的增殖、克隆形成、成瘤潜能、转移和耐药性[37]。因此,上述因子可通过正向调控Wnt/β-catenin信号通路而维持LCSC的功能和特性,对肺癌的治疗和预后判断具有重要参考价值。
此外,一些负向调控因子如Axin2、DKK3、GSK3β和上皮钙黏素(E-cadherin)等通过Wnt/β-catenin信号通路维持LCSC的功能和特性。研究发现,miR-582-3p可下调Axin2、DKK3和SFRP1的表达,促进肺癌的复发、转移和耐药[38]。相反,拮抗miR-582-3p可有效抑制异种移植瘤小鼠肺癌的发生和发展[38]。miR-19a/b可靶向抑制GSK3β的表达,激活Wnt信号通路,促进LCSC的自我更新、增殖、克隆和耐药[39]。此外,E-cadherin可抑制β-catenin从细胞膜向细胞质内转运,从而影响干细胞的功能[40]。下调肺癌A549细胞株中E-cadherin的表达,可上调巢蛋白(Nestin)、c-myc、Oct3/4和β-catenin的表达,促进CSCs的增殖、血管形成、生长和侵袭[41]。上调E-cadherin的编码基因CDH1后,可抑制Wnt/β-catenin信号通路下游靶基因的转录活性,从而抑制LCSC的增殖、转移和复发[42]。上述因子表达下调可促进Wnt/β-catenin信号通路的激活,选择性阻止其下调,可调控LCSC的干性特征,这为肺癌的治疗提供了潜在靶点。
Wnt/β-catenin信号通路激活与BCSC的功能密切相关,在BCSC的增殖、克隆和侵袭中发挥着重要作用,其机制与乳腺癌中Nestin、LGR4、LGR5和低密度脂蛋白受体相关蛋白8(low-density lipoprotein receptor-related protein 8,LRP8)的高表达有关。Nestin是一种中间丝蛋白,与恶性肿瘤的发展和转移有关。在三阴性乳腺癌中高表达的Nestin通过上调β-catenin及下调E-cadherin、Axin、GSK3β、APC和过氧化物酶体增殖物激活受体α(PPARα),引发Wnt/β-catenin信号转导和下游靶基因c-mycMMP-7MMP-2Cyclin D的转录,从而促进BCSC的存活、增殖和转移[43]。LRP8定位于乳腺癌细胞表面,具有维持BCSC特性的作用。LRP8通过增强细胞内β-catenin的活性并促使其向核内易位,使经典Wnt途径激活,增强BCSC增殖能力、异种移植模型的致瘤潜能及耐药性[10]。LGR4、LGR5是BCSC的重要标志物,可通过Wnt/β-catenin信号通路维持CSCs的干性特征,其机制为乳腺癌细胞中LGR4和LGR5过度表达,促进β-catenin向核内易位,下调E-cadherin的表达。Wnt/β-catenin信号通路激活导致下游靶基因c-mycCyclin DSnail的表达增加,可促进BCSC的自我更新、成瘤潜力、迁移和EMT[44-45]。应用LGR5抑制剂MDAMB231处理BCSC后,Wnt3a可重新激活被抑制的Wnt/β-catenin信号通路,恢复BCSC的干性特征[45]。因此,对Wnt/β-catenin信号通路某些上游因子进行调控,可能是乳腺癌治疗的新方向。
EMT过程与E-cadherin、Snail、MP-1和波形蛋白的表达密切相关,作为肿瘤侵袭和转移过程中的一个重要环节,亦受Wnt/β-catenin信号通路的调控。Wnt/β-catenin信号通路的激活使乳腺癌细胞中E-cadherin表达水平下降,Snail、波形蛋白表达水平升高,从而促进EMT的发生,同时上调CSCs标志物(ALDH1、Nanog和Oct4)的表达,最终促进BCSC的增殖、克隆形成、转移、EMT和耐药[46]。相反,通过上调DKK1阻断Wnt/β-catenin信号通路的转导,可使MP-1、Snail和波形蛋白表达下调,抑制BCSC的生长、迁移和侵袭[47]。此外,XB130可通过PI3K/Akt信号途径促进β-catenin向核内易位,维持乳腺癌细胞的EMT进程和干细胞样特性[48]。PI3K/Akt轴可激活Wnt/β-catenin信号通路,促进BCSC的增殖、转移和EMT[49]。因此,通过抑制Wnt/β-catenin信号通路的活性,靶向调节EMT相关蛋白的表达,可达到治疗乳腺癌并防止复发的效果。
Wnt/β-catenin信号通路可介导神经发育过程,也可维持GSC的生存和凋亡。有研究发现,Wnt/β-catenin信号通路激活可使β-catenin在GSC中的表达增加14倍以上,提示Wnt/β-catenin信号通路可调控GSC的活性[12]。Wnt/β-catenin信号通路激活可促进胶质母细胞瘤(glioblastoma,GMB)内ZEB1的表达和EMT的发生,促进GSC的迁移和侵袭[50]。受体样络氨酸激酶(receptor-like tyrosine kinase,PYK)在GSC中表达明显上调,使β-catenin核内易位增加,从而可改善细胞的运动性,稳定细胞的生长及促进神经球的形成,维持GMB的干细胞样特性和致瘤性[51]。Wnt1、Wnt3a在GSC中过表达,下调Wnt1、Wnt3a可降低CSC的增殖、迁移、化学抗性及体内成瘤能力[52]。有研究发现,Wnt3a可抑制GSK3β的活性,稳定细胞核内KDM4c(一种JmjC结构域组蛋白去甲基化酶)与β-catenin的相互作用,调节GSC的特性,促进肿瘤的进展[53]。因此,Wnt-KDM4c-β-catenin可能成为治疗GBM的新靶标。另外,GSC可自分泌Wnt诱导的信号蛋白1(Wnt-induced signaling protein 1,WISP1),激活Wnt/β-catenin信号通路,维持肿瘤细胞的干性特征,也可通过旁分泌形式激活Wnt/β-catenin信号通路,调节肿瘤相关巨噬细胞的活性及肿瘤细胞微环境,促进肿瘤的发生与发展。肌酸可抑制Wnt/β-catenin-WISP1信号转导,抑制肿瘤的增殖和生长[54]。由此可见,Wnt/β-catenin信号通路相关因子可作为GBM预后评估的重要指标。
此外,有研究发现,β-catenin向细胞核内转移、GSK3β下调、APC突变或EMT等也可发生在甲状腺癌干细胞、卵巢癌干细胞、前列腺癌干细胞、胃癌干细胞等[55-56]中,影响细胞的自我更新、增殖、转移和耐药。因此,Wnt/β-catenin信号通路可调控多种CSCs,在不同类型的肿瘤中发挥重要作用。
目前针对Wnt/β-catenin信号通路的抑制剂有多种类型,包括小分子抑制剂、新生血管抑制剂和重组药物(基因、病毒)等。PRI-724是一种小分子Wnt/β-catenin信号通路抑制剂,能够阻断β-catenin与下游转录因子的相互作用[57]。既往临床研究发现,PRI-724可诱导CSCs分化,增加CSCs对靶向药物的敏感性[58];其与吉西他滨联用治疗胰腺癌具有一定的效果[59]。CWP232291是一种肽类物质,能够选择性作用于Wnt/β-catenin转录产物,有效降低survivincyclin D1等基因的表达,活化内质网应激通路[60]。CWP232291治疗难治性骨髓瘤和急性髓系白血病具有良好的效果[60]。Cho等[61]发现,Wnt抑制剂与5-氟尿嘧啶(5-fluorouracil,5-FU)联合应用可通过p53的介导有效抑制CSCs,抑制停药后肿瘤的再生长,该研究强调了Wnt抑制剂与5-FU联合治疗的重要性。Wnt/β-catenin信号通路抑制剂可通过抑制该通路的活性,对某些肿瘤的预防和治疗发挥重要作用。有研究发现,依他尼酸、非甾体抗炎药、氯硝柳胺等用于治疗其他疾病的药物,也具有抑制Wnt信号通路的作用[62]。未来这些药物可能用于治疗Wnt信号通路依赖的肿瘤。
Wnt/β-catenin信号通路在CSCs中起着关键作用,可维持CSCs的自我更新、增殖和干细胞表型,还可促进CSCs的侵袭、转移和耐药。大量研究发现,阻断乳腺癌、肺癌、肠癌、GMB、宫颈癌、前列腺癌等肿瘤Wnt/β-catenin信号通路的关键上下游靶点,可抑制CSCs的自我更新、增殖、肿瘤血管生成、侵袭和扩散,有效抑制肿瘤的发生与发展,同时可降低肿瘤的耐药性,提高治疗效果。Wnt/β-catenin信号通路抑制剂可有效降低该通路的活性,有望成为治疗Wnt信号通路依赖肿瘤的突破点。然而,Wnt/β-catenin信号通路对CSCs的调控机制尚未完全阐明,从起源上识别并清除CSCs、早期预防肿瘤的发生仍是肿瘤防治的重点与难点。
  • 大连市科技创新基金(2021JJ13SN67)
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2022年第47卷第8期
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doi: 10.11855/j.issn.0577-7402.2022.08.0831
  • 接收时间:2021-06-27
  • 首发时间:2025-12-15
  • 出版时间:2022-08-28
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  • 收稿日期:2021-06-27
  • 录用日期:2021-08-10
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Dalian Science and Technology Innovation Fund Program(2021JJ13SN67)
大连市科技创新基金(2021JJ13SN67)
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    1大连医科大学附属第二医院研究生院,辽宁大连 116027
    2大连市第三人民医院呼吸与危重症医学科,辽宁大连 116091
    3大连医科大学附属第二医院健康管理中心,辽宁大连 116027

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2种不同金属材料的力学参数

Family
属数
Number of
genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)

Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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