肿瘤干细胞标志物Musashi1与实体肿瘤关系的研究进展

2015-09-05 07:00苏克举曹洪明
吉林大学学报(医学版) 2015年2期
关键词:母细胞干细胞标志物

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。

[1]Wang XY,Yin Y,Yuan H,et al. Musashi 1 modulates mammary progenitor cell expansion through proliferin-mediated activation of the wnt and notch pathways [J]. Mol Cell Biol,2008,28(11): 3589- 3599.

[2]Nakamura M,Okano H,Blendy JA,et al. A neural RNA-binding protein required for Drosophila adult external sensory organ development [J]. Neuron,1994,13(1): 67-81.

[3]Sakakibara S,Imai T,Hamaguchi K,et al. A neural RNA-binding protein highly enriched in the mammalian CNS stem cell [J]. Dev Biol,1996,176(2): 230-242.

[4]Ratti A,Fallini C,Cova L,et al. A role for the ELAV RNA-binding proteins in neural stem cells: stabilization of Msi1 mRNA[J]. J Cell Sci,2006,119(Pt7): 1442-1452.

[5]Okano H,Kawahara H,Toriya M,et al. Function of RNA-binding protein Musashi 1 in stem cells[J]. Exp Cell Res,2005,306(2): 349-356.

[6]Glazer RI,Wang XY,Yuan H,et al. Musashi1: A Stem Cell Marker No Longer in Search of a Function[J]. Cell Cycle,2008,7(17): 2635-2639.

[7]Imai T,Tokunaga A,Yoshida T,et al. The neural RNA-binding protein Musashi1 translationally regulates mammalian numb gene expression by interacting with its mRNA[J]. Mol Cell Biol,2001,21(12): 3888-3900.

[8]Okabe M,Imai T,Kurusu M,et al. Translational repression determines a neuronal potential in Drosophila asymmetric cell division[J]. Nature,2001,411(6833):94-98.

[9]Kayahara T,Sawada M,Takaishi S,et al. Candidate markers for stem and early progenitor cells,Musashi-1 and Hesl,are expressed in crypt base columnar cells of mouse small intestine [J]. FEBS Lett,2003,535(1-3):131-135.

[10]Battelli C,Nikopoulos GN,Mitchell JG,et al. The RNA-binding protein Musashi-1 regulates neural development through the translational repression of p21WAF-1[J]. Mol Cell Neurosci,2006,31(1): 85-96.

[11]Abreu RS, Sanchez-Diaz PC,Christine V,et al. Genomic analyses of musashi1 downstream targets show a strong association with cancer-related processes[J]. J Biol Chem,2009,284(18): 12125-12135.

[12]Toda M,Iizuka Y,Yu W,et al. Expression of the neural RNA-binding protein Musashi1 in human gliomas[J]. Glia,2001,34(1):1-7.

[13]Kanemura Y,Mori K,Sakakibara S,et al. Musashi1,an evolutionarily conserved neural RNA-binding protein,is a versatile marker of human glioma cells in determining their cellular origin,malignancy,and proliferative activity[J]. Differentiation,2001,68(2-3): 141-152.

[14]Yokota N,Mainprize TG,Taylor MD,et al. Identification of differentially expressed and developmentally regulated genes in medulloblastoma using suppression subtraction hybridization[J]. Oncogene,2004,23(19): 3444-3453.

[15]Nakano A,Kanemura Y,Mori K,et al. Expression of the Neural RNA-binding protein Musashi1 in pediatric brain tumors[J]. Pediatr Neurosurg,2007,43(4): 279-284.

[16]Boon K,Edwards JB,Siu IM,et al.Comparison of medulloblastoma and normal neural transcriptomes identifies a restricted set of activated genes[J]. Oncogene,2003,22(48): 7687-7694 .

[17]Ma YH,Mentlein R,Knerlich F,et al.Expression of stem cell markers in human astrocytomas of different WHO grades[J]. J Neurooncol,2008,86(1):31-45.

[18]Seigel GM,Hackam AS,Ganguly A,et al. Human embryonic and neuronal stem cell markers in retinoblastoma[J]. Mol Vis,2007,13:823-832.

[19]Sanchez-Diaz PC,Burton TL,Burns SC,et al. Musashi1 modulates cell proliferation genes in the medulloblastoma cell line Daoy [J]. BMC Genetics,2008,9:280-291.

[20]Shu HJ,Saito T,Watanabe H,et al. Expression of the Musashi1 gene encoding the RNA-binding protein in human hepatoma cell lines [J]. Biochem Biophys Res Commun,2002,293(1):150-154.

[21]Fan LF,Dong WG,Jiang CQ,et al. Expression of putative stem cell genes Musashi-1 and beta1-integrin in human colorectal adenomas and adenocarcinomas [J]. Int J Colorect Dis,2010,25(1):17-23.

[22]Li D,Peng X,Yan D,et al. Msi-1 is a predictor of survival and a novel therapeutic target in colon cancer [J].Ann Sug Oncol,2011,18(7):2074-2083.

[23] Bobryshev YV,Freeman AK,Botelho NK,et al. Expression of the putative stem cell marker Musashi-1 in Barrett’s esophagus and esophageal adenocarcinoma [J]. Dis Esophagus,2010,23(7):580-589.

[24]Vega KJ,May R,Sureban SM,et al. Identification of the putative intestinal stem cell marker DCAMKL-1 in Barrett’s esophagus and esophageal adenocarcinoma [J]. Gastroenterol Hepatol,2012,27(4):773-780.

[25]Schmuck R,Warneke V,Behrens HM,et al. Genotypic and phenotypic characterization of side population of gastric cancer cell lines [J]. Am J Pathol,2011,178(4):1792-1804.

[26]Wang T,Ong CW,Shi J,et al. Sequential expression of putative stem cell markers in gastric carcinogenesis [J]. Br J Cancer,2011,105(5):658-665.

[27]Lewis A,Segditsas S,Deheragoda M,et al. Severe polyposis in Apc(1322 T) mice is associated with submaximal Wnt signalling and increased expression of the stem cell marker Lgr5 [J]. Gut,2010,59(12):1680-1686.

[28]Todaro M,Alea MP,Di Stefano AB,et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4 [J]. Cell Stem Cell,2007,1(4):389-402.

[29]Li YQ,Wu CT,Wu Y,et al. The expression of Msi-1 and its significance in small intestinal mucosa severely damaged by high-dose 5-FU [J]. Dig Dis Sci,2008,53(9):2436-2442.

[30]Wang XY,Penalva LO,Yuan HY,et al. Musashi1 regulates breast tumor cell proliferation and is a prognostic indicator of poor survival [J]. Mol Cancer,2010,9:221.

[31]Moreira AL,Gonen M,Rekhtman N,et al. Progenitor stem cell marker expression by pulmonary carcinomas [J]. Mod Pathol,2010,23(6):889-895.

[32]Kanai R,Eguchi K,Takahashi M,et al. Enhanced therapeutic efficacy of oncolytic herpes vector G207 against human non-small cell lung cancer-expression of an RNA-binding protein,Musashi1,as a marker for the tailored gene therapy[J]. J Gene Med,2006,8(11):1329-1340.

[33]Wang XY,Yu H,Linnoila RI,et al.Musashi1 as a potential therapeutic target and diagnostic marker for lung cancer[J]. Oncotarget,2013,4(5): 739-750.

[34]Ye F,Zhou C,Cheng Q,et al. Stem-cell-abundant proteins Nanog,nucleostemin and Musashi1 are highly expressed in malignant cervical epithelial cells[J].BMC Cancer,2008,8:108.

[35]Gotte M,Wolf M,Staebler A,et al. Increased expression of the adult stem cell marker Musashi-1 in endometriosis and endometrial carcinoma[J]. J Pathol,2008,215(3):317-329.

[36]Cervello I,Mirantes C,Santamaria X,et al. Stem cells in human endometrium and endometrial carcinoma[J]. Int J Gynecol Pathol,2011,30(4):317-327.

[37]Okuno K,Ohta S,Kato H,et al. Expression of neural stem cell markers in malignant rhabdoid tumor cell lines[J]. Oncol Rep,2010,23(2):485-492.

[38]Ravindran G,Devaraj H. Aberrant expression of CD133 and musashi-1 in preneoplastic and neoplastic human oral squamous epithelium and their correlation with clinicopathological factors[J]. Head Neck,2012,34(8):1129-1135.

[39]Thill M,Berna MJ,Grierson R,et al. Expression of CD133 and other putative stem cell markers in uveal melanoma[J]. Melanoma Res,2011,21(5):405-416.

[40]Nikpour P,Baygi ME,Steinhoff C,et al.The RNA binding protein musashi1 regulates apoptosis,gene expression and stress granule formation in urothelial carcinoma cells[J]. J Cell Mol Med,2011,15(5):1210-1224.

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 )

R73

A

猜你喜欢
母细胞干细胞标志物
干细胞:“小细胞”造就“大健康”
成人幕上髓母细胞瘤1例误诊分析
顶骨炎性肌纤维母细胞瘤一例
造血干细胞移植与捐献
髓外硬膜内软骨母细胞瘤1例
预防小儿母细胞瘤,10个细节别忽视
干细胞产业的春天来了?
脓毒症早期诊断标志物的回顾及研究进展
冠状动脉疾病的生物学标志物
肿瘤标志物在消化系统肿瘤早期诊断中的应用