腫瘤干細胞標志物Musashi1與實體腫瘤關系的研究進展

蘇克舉，王　旭，何　華，曹洪明，李　薇

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

腫瘤干細胞標志物Musashi1與實體腫瘤關系的研究進展

蘇克舉1，王旭1，何華1，曹洪明2，李薇1

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

Musashi1 (Msi1)是一種最新研究報道的腫瘤干細胞(TSC)標志物，其在Notch和Wnt/β-catenin等信號通路中發揮重要作用，并與多種實體腫瘤的發病、轉移和預后有密切關聯。詳細研究Msi1的結構與功能及其在惡性腫瘤中的表達,有助于明確Msi1在惡性腫瘤發生發展中的作用。本文作者對Msi1的作用機制、Msi1與多種實體腫瘤發生發展關系這兩個方面的研究現狀進行綜述。

Musashi1;實體腫瘤;腫瘤

腫瘤干細胞研究是近年來腫瘤研究的一個新熱點， Musashi1 (Msi1)是一種最新研究報道的腫瘤干細胞(tumor stem cell，TSC)標志物。正常情況下，干細胞的更新、分化能力受到信號傳導途徑的嚴格控制。當信號傳導通路表達失調或相關基因突變，即會導致這些調控機制異常，引起細胞分化異常，無限增殖，形成TSC。TSC在腫瘤組織中數量稀少，但具備自我更新、增殖和分化潛能，在腫瘤的發生發展、轉移和復發中起重要作用。目前，已被證實的與TSC有密切關聯的細胞信號通路有Notch和Wnt/β-catenin和Hedgehog 信號通路。研究[1]表明：Msi1在Notch和Wnt/β-catenin等信號通路中發揮重要作用，與TSC的發生有發展密切關聯。本文就Msi1與腫瘤關系的研究進展作一綜述。

1　Msi1的結構與功能

Msi1基因位于12q24和1q24.31，其包含14個外顯子。Msi1首次是在果蠅屬種發現[2]，是一種進化上保守的RNA結合蛋白[3]。Msi1被證實是哺乳動物神經干細胞的一個重要標記物[4]，研究[5]顯示：Msi1亦表達于乳腺、胃腸道和皮膚等干細胞,是人類干細胞的一般標記。人Msi1由362個氨基酸組成，N端含有2個保守的RRM(RNA recognize domain)結構域。Msi1通過RRM結構域與靶基因mRNA相互作用,從翻譯水平調節靶基因的表達。目前的研究[6]結果提示：Msi1主要通過Notch信號通路和Wnt信號通路來發揮其作用(以乳腺干細胞為例，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,促進細胞的自我更新、不斷增殖和分化潛能[7-8]； ② Msi1轉錄激活后,即與Notch信號通路的Hes l基因特異性結合,促進腫瘤的形成和發展[9]；③ Msi1能通過調節細胞自身分泌激活Wnt信號通路,從而抑制Wnt通路中的拮抗因子DKK3的分泌,促進多育曲菌素1(Proliferin-1,PLF1)分泌,破壞了復合體Axin-APC-GSK3β,使β-catenin/TCG激活后[1],胞漿內部的β-catenin即進入胞核,激活下游目的基因的轉錄,從而啟動癌基因的啟動子密碼,發生癌變；④ Msi1結合到3′-UTR上的特征序列,抑制P21的表達,參與細胞周期的調控[10]。Msi1的作用機制復雜，目前有許多機制尚不清楚，有研究[11]應用Pathway Studio軟件預測了Msi1相關靶基因mRNAs編碼的蛋白質靶點，這些靶點主要與細胞周期、凋亡和增殖有關聯。

2　Msi1與實體腫瘤發生發展的關系

Msi1在轉錄后基因調節階段調控細胞的非對稱分裂，在維持干細胞增殖和分化以及腫瘤發生方面起重要作用[1]。目前Msi1與腫瘤的研究進展主要表現在以下幾個方面。

2.1Msi1與腦腫瘤Msi1表達增加最初是在膠質母細胞瘤中發現的。Toda 等[12]與Kanemura 等[13]報道：Msi1在神經膠質瘤中呈高表達；Yokota 等[14]、Nakano 等[15]和Boon 等[16]發現髓母細胞瘤中Msi1的表達較周圍正常組織高；Ma等[17]發現：Msi1在星形細胞瘤中呈高表達；Seigel等[18]的研究表明：Msi1在視網膜母細胞瘤中呈高表達。有研究[15，19]表明：Msi1高水平表達提示神經膠質瘤與星形細胞瘤預后不良相關，且Msi1表達的增加與Notch1的表達水平、腫瘤增殖和浸潤相關[14]。通過抑制性消減雜交方法證明了在髓母細胞瘤細胞中存在Msi1和Notch信號通路的激活[15]。Patricia等[19]的研究表明：在Daoy人髓母細胞瘤細胞中，Msi1的表達水平增高，且其可能與癌細胞的增殖調控相關聯。通過RNA干擾方法下調Daoy人髓母細胞瘤細胞中Msi1的表達會明顯降低其在軟瓊脂上形成克隆的能力，同時亦會下調其在培養皿中形成神經球的能力，這表明Msi1可能在髓母細胞瘤這一亞型的發病中發揮了重要的作用。

圖1　Msi1信號通路在乳腺干細胞增殖過程中的作用

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

2.2Msi1與消化系統惡性腫瘤大量研究[20-26]表明：Msi1在消化系統惡性腫瘤中呈高表達，如肝細胞癌、結直腸癌、食管腺癌及其癌前病變和胃癌。在動物模型中，一種更具侵襲性的腫瘤表型與腸干細胞標記物Lgr5的表達水平增加有關聯，同樣Msi1表達亦增加[27]。近期有研究[23-24]顯示：Msi1表達增高與結腸癌的TNM分期直接相關。CD133與Msi1雙陽性表達的結腸癌細胞對奧沙利鉑聯合5-氟尿嘧啶方案化療高度耐藥[28]，該結果與Li等[29]研究結果一致，提示Msi1表達與腫瘤耐藥相關。此外Msi1表達增高亦與Ki-67表達陽性及結腸癌的預后不良相關[24]。

2.3Msi1與乳腺癌Wang等[30]發現:在乳腺癌組織中，40%原發腫瘤和100%轉移淋巴結中Msi1呈高表達，活化的Msi1可激活Wnt和Notch 通路，促進腫瘤的發生發展。敲除Msi1基因或降低Msi1表達，可以通過阻止腫瘤異形嫁接物的生長、誘導癌癥細胞凋亡、阻止有絲分裂和細胞周期進程，抑制腫瘤細胞增殖并導致腫瘤消退。Msi1能誘導腫瘤轉移和導致腫瘤細胞耐藥，最終影響腫瘤預后。

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胞呈Msi1陽性表達；而100%小細胞肺癌呈彌漫Msi1陽性表達；4%腺癌存在彌漫Msi1陽性表達，36%腺癌存在局灶Msi1陽性表達，22%腺癌存在孤立Msi1陽性表達；27%大細胞癌存在彌漫Msi1陽性表達，36%大細胞癌存在局灶Msi1陽性表達，9%大細胞癌存在孤立Msi1陽性表達；36%鱗狀細胞癌呈局灶Msi1陽性表達，27%鱗狀細胞癌存在孤立Msi1陽性表達。Kanai等[32]報道：Msi1在Lu-99肺癌細胞系、肺腺癌和大細胞癌組織中陽性表達。近期Wang 等[33]進行了一項研究，旨在鑒定與肺癌相關的干祖細胞標志物，結果表明:Msi1可作為肺癌的診斷標記，并有望成為潛在的治療靶點。

2.5Msi1與其他惡性腫瘤研究者就Msi1與惡性腫瘤進行了廣泛的研究，證實在宮頸癌[34]、子宮內膜癌[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表達增高。

3　結　語

綜上所述，Msi1通過對多種基因的轉錄后調控參與了腫瘤的發生發展和轉移等過程，且與腫瘤的預后及治療有關聯。然而目前Msi1的生物學功能及其分子機制尚不完全清楚，對Msi1調控機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

衛生與計劃生育委員會醫院臨床學科重點項目資助課題(2001133)

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

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

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