肿瘤干细胞标志物Musashi1与实体肿瘤关系的研究进展

苏克举，王　旭，何　华，曹洪明，李　薇

(1.吉林大学第一医院肿瘤中心,吉林 长春 130021；2. 吉化集团公司总医院放疗科,吉林 吉林 132021)

肿瘤干细胞标志物Musashi1与实体肿瘤关系的研究进展

苏克举1，王旭1，何华1，曹洪明2，李薇1

(1.吉林大学第一医院肿瘤中心,吉林 长春 130021；2. 吉化集团公司总医院放疗科,吉林 吉林 132021)

Musashi1 (Msi1)是一种最新研究报道的肿瘤干细胞(TSC)标志物，其在Notch和Wnt/β-catenin等信号通路中发挥重要作用，并与多种实体肿瘤的发病、转移和预后有密切关联。详细研究Msi1的结构与功能及其在恶性肿瘤中的表达,有助于明确Msi1在恶性肿瘤发生发展中的作用。本文作者对Msi1的作用机制、Msi1与多种实体肿瘤发生发展关系这两个方面的研究现状进行综述。

Musashi1;实体肿瘤;肿瘤

肿瘤干细胞研究是近年来肿瘤研究的一个新热点， Musashi1 (Msi1)是一种最新研究报道的肿瘤干细胞(tumor stem cell，TSC)标志物。正常情况下，干细胞的更新、分化能力受到信号传导途径的严格控制。当信号传导通路表达失调或相关基因突变，即会导致这些调控机制异常，引起细胞分化异常，无限增殖，形成TSC。TSC在肿瘤组织中数量稀少，但具备自我更新、增殖和分化潜能，在肿瘤的发生发展、转移和复发中起重要作用。目前，已被证实的与TSC有密切关联的细胞信号通路有Notch和Wnt/β-catenin和Hedgehog 信号通路。研究[1]表明：Msi1在Notch和Wnt/β-catenin等信号通路中发挥重要作用，与TSC的发生有发展密切关联。本文就Msi1与肿瘤关系的研究进展作一综述。

1　Msi1的结构与功能

Msi1基因位于12q24和1q24.31，其包含14个外显子。Msi1首次是在果蝇属种发现[2]，是一种进化上保守的RNA结合蛋白[3]。Msi1被证实是哺乳动物神经干细胞的一个重要标记物[4]，研究[5]显示：Msi1亦表达于乳腺、胃肠道和皮肤等干细胞,是人类干细胞的一般标记。人Msi1由362个氨基酸组成，N端含有2个保守的RRM(RNA recognize domain)结构域。Msi1通过RRM结构域与靶基因mRNA相互作用,从翻译水平调节靶基因的表达。目前的研究[6]结果提示：Msi1主要通过Notch信号通路和Wnt信号通路来发挥其作用(以乳腺干细胞为例，见图1)：① Notch信号通路中存在一种抑制因子即m-Numb,在激活Msi1后,m-Numb的翻译过程即被阻断,从而激活Notch信号通路,促进细胞的自我更新、不断增殖和分化潜能[7-8]； ② Msi1转录激活后,即与Notch信号通路的Hes l基因特异性结合,促进肿瘤的形成和发展[9]；③ Msi1能通过调节细胞自身分泌激活Wnt信号通路,从而抑制Wnt通路中的拮抗因子DKK3的分泌,促进多育曲菌素1(Proliferin-1,PLF1)分泌,破坏了复合体Axin-APC-GSK3β,使β-catenin/TCG激活后[1],胞浆内部的β-catenin即进入胞核,激活下游目的基因的转录,从而启动癌基因的启动子密码,发生癌变；④ Msi1结合到3′-UTR上的特征序列,抑制P21的表达,参与细胞周期的调控[10]。Msi1的作用机制复杂，目前有许多机制尚不清楚，有研究[11]应用Pathway Studio软件预测了Msi1相关靶基因mRNAs编码的蛋白质靶点，这些靶点主要与细胞周期、凋亡和增殖有关联。

2　Msi1与实体肿瘤发生发展的关系

Msi1在转录后基因调节阶段调控细胞的非对称分裂，在维持干细胞增殖和分化以及肿瘤发生方面起重要作用[1]。目前Msi1与肿瘤的研究进展主要表现在以下几个方面。

2.1Msi1与脑肿瘤Msi1表达增加最初是在胶质母细胞瘤中发现的。Toda 等[12]与Kanemura 等[13]报道：Msi1在神经胶质瘤中呈高表达；Yokota 等[14]、Nakano 等[15]和Boon 等[16]发现髓母细胞瘤中Msi1的表达较周围正常组织高；Ma等[17]发现：Msi1在星形细胞瘤中呈高表达；Seigel等[18]的研究表明：Msi1在视网膜母细胞瘤中呈高表达。有研究[15，19]表明：Msi1高水平表达提示神经胶质瘤与星形细胞瘤预后不良相关，且Msi1表达的增加与Notch1的表达水平、肿瘤增殖和浸润相关[14]。通过抑制性消减杂交方法证明了在髓母细胞瘤细胞中存在Msi1和Notch信号通路的激活[15]。Patricia等[19]的研究表明：在Daoy人髓母细胞瘤细胞中，Msi1的表达水平增高，且其可能与癌细胞的增殖调控相关联。通过RNA干扰方法下调Daoy人髓母细胞瘤细胞中Msi1的表达会明显降低其在软琼脂上形成克隆的能力，同时亦会下调其在培养皿中形成神经球的能力，这表明Msi1可能在髓母细胞瘤这一亚型的发病中发挥了重要的作用。

图1　Msi1信号通路在乳腺干细胞增殖过程中的作用

Fig.1Effect of Msi1 signaling pathway in poliferation of breast stem cells

2.2Msi1与消化系统恶性肿瘤大量研究[20-26]表明：Msi1在消化系统恶性肿瘤中呈高表达，如肝细胞癌、结直肠癌、食管腺癌及其癌前病变和胃癌。在动物模型中，一种更具侵袭性的肿瘤表型与肠干细胞标记物Lgr5的表达水平增加有关联，同样Msi1表达亦增加[27]。近期有研究[23-24]显示：Msi1表达增高与结肠癌的TNM分期直接相关。CD133与Msi1双阳性表达的结肠癌细胞对奥沙利铂联合5-氟尿嘧啶方案化疗高度耐药[28]，该结果与Li等[29]研究结果一致，提示Msi1表达与肿瘤耐药相关。此外Msi1表达增高亦与Ki-67表达阳性及结肠癌的预后不良相关[24]。

2.3Msi1与乳腺癌Wang等[30]发现:在乳腺癌组织中，40%原发肿瘤和100%转移淋巴结中Msi1呈高表达，活化的Msi1可激活Wnt和Notch 通路，促进肿瘤的发生发展。敲除Msi1基因或降低Msi1表达，可以通过阻止肿瘤异形嫁接物的生长、诱导癌症细胞凋亡、阻止有丝分裂和细胞周期进程，抑制肿瘤细胞增殖并导致肿瘤消退。Msi1能诱导肿瘤转移和导致肿瘤细胞耐药，最终影响肿瘤预后。

2.4Msi1与肺癌Moreira等[31]研究表明：正常肺组织的终末支气管可见散在细胞呈Msi1阳性表达；而100%小细胞肺癌呈弥漫Msi1阳性表达；4%腺癌存在弥漫Msi1阳性表达，36%腺癌存在局灶Msi1阳性表达，22%腺癌存在孤立Msi1阳性表达；27%大细胞癌存在弥漫Msi1阳性表达，36%大细胞癌存在局灶Msi1阳性表达，9%大细胞癌存在孤立Msi1阳性表达；36%鳞状细胞癌呈局灶Msi1阳性表达，27%鳞状细胞癌存在孤立Msi1阳性表达。Kanai等[32]报道：Msi1在Lu-99肺癌细胞系、肺腺癌和大细胞癌组织中阳性表达。近期Wang 等[33]进行了一项研究，旨在鉴定与肺癌相关的干祖细胞标志物，结果表明:Msi1可作为肺癌的诊断标记，并有望成为潜在的治疗靶点。

2.5Msi1与其他恶性肿瘤研究者就Msi1与恶性肿瘤进行了广泛的研究，证实在宫颈癌[34]、子宫内膜癌[35-36]、恶性横纹肌样瘤[37]、口腔癌[38]、葡萄膜黑色素瘤[39]和膀胱癌[40]等恶性肿瘤中亦存在Msi1表达增高。

3　结　语

综上所述，Msi1通过对多种基因的转录后调控参与了肿瘤的发生发展和转移等过程，且与肿瘤的预后及治疗有关联。然而目前Msi1的生物学功能及其分子机制尚不完全清楚，对Msi1调控机制的研究有望为临床诊断和治疗肿瘤提供新思路。

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Advance research on relationship between tumor stem cell marker Musashi1 and solid tumor

1671-587Ⅹ(2015)02-0429-04

10.13481/j.1671-587x.20150245

2014-03-10

卫生与计划生育委员会医院临床学科重点项目资助课题(2001133)

苏克举(1987-)，男，吉林省长春市人，在读医学硕士，主要从事临床恶性肿瘤内科方面的研究。

李薇，教授，博士研究生导师(Tel：0431-88782180，E-mail：drweili@yahoo.com )

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