腫瘤干細(xì)胞標(biāo)志物Musashi1與實(shí)體腫瘤關(guān)系的研究進(jìn)展

蘇克舉，王　旭，何　華，曹洪明，李　薇

(1.吉林大學(xué)第一醫(yī)院腫瘤中心,吉林 長春 130021；2. 吉化集團(tuán)公司總醫(yī)院放療科,吉林 吉林 132021)

腫瘤干細(xì)胞標(biāo)志物Musashi1與實(shí)體腫瘤關(guān)系的研究進(jìn)展

蘇克舉1，王旭1，何華1，曹洪明2，李薇1

(1.吉林大學(xué)第一醫(yī)院腫瘤中心,吉林 長春 130021；2. 吉化集團(tuán)公司總醫(yī)院放療科,吉林 吉林 132021)

Musashi1 (Msi1)是一種最新研究報(bào)道的腫瘤干細(xì)胞(TSC)標(biāo)志物，其在Notch和Wnt/β-catenin等信號通路中發(fā)揮重要作用，并與多種實(shí)體腫瘤的發(fā)病、轉(zhuǎn)移和預(yù)后有密切關(guān)聯(lián)。詳細(xì)研究Msi1的結(jié)構(gòu)與功能及其在惡性腫瘤中的表達(dá),有助于明確Msi1在惡性腫瘤發(fā)生發(fā)展中的作用。本文作者對Msi1的作用機(jī)制、Msi1與多種實(shí)體腫瘤發(fā)生發(fā)展關(guān)系這兩個(gè)方面的研究現(xiàn)狀進(jìn)行綜述。

Musashi1;實(shí)體腫瘤;腫瘤

腫瘤干細(xì)胞研究是近年來腫瘤研究的一個(gè)新熱點(diǎn)， Musashi1 (Msi1)是一種最新研究報(bào)道的腫瘤干細(xì)胞(tumor stem cell，TSC)標(biāo)志物。正常情況下，干細(xì)胞的更新、分化能力受到信號傳導(dǎo)途徑的嚴(yán)格控制。當(dāng)信號傳導(dǎo)通路表達(dá)失調(diào)或相關(guān)基因突變，即會導(dǎo)致這些調(diào)控機(jī)制異常，引起細(xì)胞分化異常，無限增殖，形成TSC。TSC在腫瘤組織中數(shù)量稀少，但具備自我更新、增殖和分化潛能，在腫瘤的發(fā)生發(fā)展、轉(zhuǎn)移和復(fù)發(fā)中起重要作用。目前，已被證實(shí)的與TSC有密切關(guān)聯(lián)的細(xì)胞信號通路有Notch和Wnt/β-catenin和Hedgehog 信號通路。研究[1]表明：Msi1在Notch和Wnt/β-catenin等信號通路中發(fā)揮重要作用，與TSC的發(fā)生有發(fā)展密切關(guān)聯(lián)。本文就Msi1與腫瘤關(guān)系的研究進(jìn)展作一綜述。

1　Msi1的結(jié)構(gòu)與功能

Msi1基因位于12q24和1q24.31，其包含14個(gè)外顯子。Msi1首次是在果蠅屬種發(fā)現(xiàn)[2]，是一種進(jìn)化上保守的RNA結(jié)合蛋白[3]。Msi1被證實(shí)是哺乳動(dòng)物神經(jīng)干細(xì)胞的一個(gè)重要標(biāo)記物[4]，研究[5]顯示：Msi1亦表達(dá)于乳腺、胃腸道和皮膚等干細(xì)胞,是人類干細(xì)胞的一般標(biāo)記。人Msi1由362個(gè)氨基酸組成，N端含有2個(gè)保守的RRM(RNA recognize domain)結(jié)構(gòu)域。Msi1通過RRM結(jié)構(gòu)域與靶基因mRNA相互作用,從翻譯水平調(diào)節(jié)靶基因的表達(dá)。目前的研究[6]結(jié)果提示：Msi1主要通過Notch信號通路和Wnt信號通路來發(fā)揮其作用(以乳腺干細(xì)胞為例，見圖1)：① Notch信號通路中存在一種抑制因子即m-Numb,在激活Msi1后,m-Numb的翻譯過程即被阻斷,從而激活Notch信號通路,促進(jìn)細(xì)胞的自我更新、不斷增殖和分化潛能[7-8]； ② Msi1轉(zhuǎn)錄激活后,即與Notch信號通路的Hes l基因特異性結(jié)合,促進(jìn)腫瘤的形成和發(fā)展[9]；③ Msi1能通過調(diào)節(jié)細(xì)胞自身分泌激活Wnt信號通路,從而抑制Wnt通路中的拮抗因子DKK3的分泌,促進(jìn)多育曲菌素1(Proliferin-1,PLF1)分泌,破壞了復(fù)合體Axin-APC-GSK3β,使β-catenin/TCG激活后[1],胞漿內(nèi)部的β-catenin即進(jìn)入胞核,激活下游目的基因的轉(zhuǎn)錄,從而啟動(dòng)癌基因的啟動(dòng)子密碼,發(fā)生癌變；④ Msi1結(jié)合到3′-UTR上的特征序列,抑制P21的表達(dá),參與細(xì)胞周期的調(diào)控[10]。Msi1的作用機(jī)制復(fù)雜，目前有許多機(jī)制尚不清楚，有研究[11]應(yīng)用Pathway Studio軟件預(yù)測了Msi1相關(guān)靶基因mRNAs編碼的蛋白質(zhì)靶點(diǎn)，這些靶點(diǎn)主要與細(xì)胞周期、凋亡和增殖有關(guān)聯(lián)。

2　Msi1與實(shí)體腫瘤發(fā)生發(fā)展的關(guān)系

Msi1在轉(zhuǎn)錄后基因調(diào)節(jié)階段調(diào)控細(xì)胞的非對稱分裂，在維持干細(xì)胞增殖和分化以及腫瘤發(fā)生方面起重要作用[1]。目前Msi1與腫瘤的研究進(jìn)展主要表現(xiàn)在以下幾個(gè)方面。

2.1Msi1與腦腫瘤Msi1表達(dá)增加最初是在膠質(zhì)母細(xì)胞瘤中發(fā)現(xiàn)的。Toda 等[12]與Kanemura 等[13]報(bào)道：Msi1在神經(jīng)膠質(zhì)瘤中呈高表達(dá)；Yokota 等[14]、Nakano 等[15]和Boon 等[16]發(fā)現(xiàn)髓母細(xì)胞瘤中Msi1的表達(dá)較周圍正常組織高；Ma等[17]發(fā)現(xiàn)：Msi1在星形細(xì)胞瘤中呈高表達(dá)；Seigel等[18]的研究表明：Msi1在視網(wǎng)膜母細(xì)胞瘤中呈高表達(dá)。有研究[15，19]表明：Msi1高水平表達(dá)提示神經(jīng)膠質(zhì)瘤與星形細(xì)胞瘤預(yù)后不良相關(guān)，且Msi1表達(dá)的增加與Notch1的表達(dá)水平、腫瘤增殖和浸潤相關(guān)[14]。通過抑制性消減雜交方法證明了在髓母細(xì)胞瘤細(xì)胞中存在Msi1和Notch信號通路的激活[15]。Patricia等[19]的研究表明：在Daoy人髓母細(xì)胞瘤細(xì)胞中，Msi1的表達(dá)水平增高，且其可能與癌細(xì)胞的增殖調(diào)控相關(guān)聯(lián)。通過RNA干擾方法下調(diào)Daoy人髓母細(xì)胞瘤細(xì)胞中Msi1的表達(dá)會明顯降低其在軟瓊脂上形成克隆的能力，同時(shí)亦會下調(diào)其在培養(yǎng)皿中形成神經(jīng)球的能力，這表明Msi1可能在髓母細(xì)胞瘤這一亞型的發(fā)病中發(fā)揮了重要的作用。

圖1　Msi1信號通路在乳腺干細(xì)胞增殖過程中的作用

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

2.2Msi1與消化系統(tǒng)惡性腫瘤大量研究[20-26]表明：Msi1在消化系統(tǒng)惡性腫瘤中呈高表達(dá)，如肝細(xì)胞癌、結(jié)直腸癌、食管腺癌及其癌前病變和胃癌。在動(dòng)物模型中，一種更具侵襲性的腫瘤表型與腸干細(xì)胞標(biāo)記物L(fēng)gr5的表達(dá)水平增加有關(guān)聯(lián)，同樣Msi1表達(dá)亦增加[27]。近期有研究[23-24]顯示：Msi1表達(dá)增高與結(jié)腸癌的TNM分期直接相關(guān)。CD133與Msi1雙陽性表達(dá)的結(jié)腸癌細(xì)胞對奧沙利鉑聯(lián)合5-氟尿嘧啶方案化療高度耐藥[28]，該結(jié)果與Li等[29]研究結(jié)果一致，提示Msi1表達(dá)與腫瘤耐藥相關(guān)。此外Msi1表達(dá)增高亦與Ki-67表達(dá)陽性及結(jié)腸癌的預(yù)后不良相關(guān)[24]。

2.3Msi1與乳腺癌Wang等[30]發(fā)現(xiàn):在乳腺癌組織中，40%原發(fā)腫瘤和100%轉(zhuǎn)移淋巴結(jié)中Msi1呈高表達(dá)，活化的Msi1可激活Wnt和Notch 通路，促進(jìn)腫瘤的發(fā)生發(fā)展。敲除Msi1基因或降低Msi1表達(dá)，可以通過阻止腫瘤異形嫁接物的生長、誘導(dǎo)癌癥細(xì)胞凋亡、阻止有絲分裂和細(xì)胞周期進(jìn)程，抑制腫瘤細(xì)胞增殖并導(dǎo)致腫瘤消退。Msi1能誘導(dǎo)腫瘤轉(zhuǎn)移和導(dǎo)致腫瘤細(xì)胞耐藥，最終影響腫瘤預(yù)后。

2.4Msi1與肺癌Moreira等[31]研究表明：正常肺組織的終末支氣管可見散在細(xì)胞呈Msi1陽性表達(dá)；而100%小細(xì)胞肺癌呈彌漫Msi1陽性表達(dá)；4%腺癌存在彌漫Msi1陽性表達(dá)，36%腺癌存在局灶Msi1陽性表達(dá)，22%腺癌存在孤立Msi1陽性表達(dá)；27%大細(xì)胞癌存在彌漫Msi1陽性表達(dá)，36%大細(xì)胞癌存在局灶Msi1陽性表達(dá)，9%大細(xì)胞癌存在孤立Msi1陽性表達(dá)；36%鱗狀細(xì)胞癌呈局灶Msi1陽性表達(dá)，27%鱗狀細(xì)胞癌存在孤立Msi1陽性表達(dá)。Kanai等[32]報(bào)道：Msi1在Lu-99肺癌細(xì)胞系、肺腺癌和大細(xì)胞癌組織中陽性表達(dá)。近期Wang 等[33]進(jìn)行了一項(xiàng)研究，旨在鑒定與肺癌相關(guān)的干祖細(xì)胞標(biāo)志物，結(jié)果表明:Msi1可作為肺癌的診斷標(biāo)記，并有望成為潛在的治療靶點(diǎn)。

2.5Msi1與其他惡性腫瘤研究者就Msi1與惡性腫瘤進(jìn)行了廣泛的研究，證實(shí)在宮頸癌[34]、子宮內(nèi)膜癌[35-36]、惡性橫紋肌樣瘤[37]、口腔癌[38]、葡萄膜黑色素瘤[39]和膀胱癌[40]等惡性腫瘤中亦存在Msi1表達(dá)增高。

3　結(jié)　語

綜上所述，Msi1通過對多種基因的轉(zhuǎn)錄后調(diào)控參與了腫瘤的發(fā)生發(fā)展和轉(zhuǎn)移等過程，且與腫瘤的預(yù)后及治療有關(guān)聯(lián)。然而目前Msi1的生物學(xué)功能及其分子機(jī)制尚不完全清楚，對Msi1調(diào)控機(jī)制的研究有望為臨床診斷和治療腫瘤提供新思路。

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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

衛(wèi)生與計(jì)劃生育委員會醫(yī)院臨床學(xué)科重點(diǎn)項(xiàng)目資助課題(2001133)

蘇克舉(1987-)，男，吉林省長春市人，在讀醫(yī)學(xué)碩士，主要從事臨床惡性腫瘤內(nèi)科方面的研究。

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

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