miRNA在膀胱癌發(fā)生發(fā)展及臨床應(yīng)用的研究進(jìn)展

李月喜(綜述)，盧鴻雁，宋東奎※(審校)

(1.河南大學(xué)淮河醫(yī)院神經(jīng)外科，河南 開封 475000；2.鄭州大學(xué)第一附屬醫(yī)院泌尿外科五病區(qū),鄭州 450052)

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miRNA在膀胱癌發(fā)生發(fā)展及臨床應(yīng)用的研究進(jìn)展

李月喜1△(綜述)，盧鴻雁2，宋東奎2※(審校)

(1.河南大學(xué)淮河醫(yī)院神經(jīng)外科，河南 開封 475000；2.鄭州大學(xué)第一附屬醫(yī)院泌尿外科五病區(qū),鄭州 450052)

膀胱癌的發(fā)生、發(fā)展與微RNA(miRNA)的異常表達(dá)密切相關(guān)，因此miRNA可作為膀胱癌診治的潛在生物學(xué)靶點(diǎn)；近年來膀胱癌相關(guān)miRNA的作用靶點(diǎn)及分子靶向機(jī)制不斷被發(fā)現(xiàn)，了解miRNA在膀胱癌發(fā)生發(fā)展中的作用的同時，尿液和血液中膀胱癌相關(guān)的miRNA的研究為膀胱癌的早期診斷奠定基礎(chǔ)。miRNA與膀胱癌的進(jìn)一步研究將為膀胱癌的早期診斷、基因靶向治療、預(yù)后評估提供新的方向。

膀胱癌；微小RNA；生物學(xué)靶點(diǎn)

膀胱癌是泌尿生殖系統(tǒng)最常見的腫瘤，發(fā)病率及病死率均占泌尿系統(tǒng)疾病的首位。微RNA(micro RNA，miRNA) 是一類高度保守的大小為19～25個核苷酸的非編碼小分子RNA，普遍存在于各種生物細(xì)胞中，參與細(xì)胞轉(zhuǎn)錄后基因表達(dá)的調(diào)控，從而參與細(xì)胞增殖、分化和凋亡。近年來miRNA與膀胱癌的研究，特別是miRNA作用靶點(diǎn)、生物學(xué)機(jī)制方面的研究，可能將為膀胱癌的早期診治靶點(diǎn)，現(xiàn)結(jié)合近年來對miRNA在膀胱癌的研究進(jìn)展予以綜述。

1 miRNA的生成過程及生物學(xué)作用

miRNA前體首先在細(xì)胞核中RNA聚合酶Ⅱ的作用下被轉(zhuǎn)錄生成1000～3000個核苷酸的初級轉(zhuǎn)錄本(pri-miRNA)。pri-miRNA又在RNA聚合酶Ⅲ作用下形成70～100個核苷酸的微小核糖核酸前體(pre-miRNA)。pre-miRNA運(yùn)輸?shù)郊?xì)胞質(zhì)中，裂解成一種19～25個核苷酸的成熟miRNA。成熟的miRNA與生物酶結(jié)合形成RNA誘導(dǎo)沉默復(fù)合物，并使RNA誘導(dǎo)沉默復(fù)合物與靶mRNA的序列互補(bǔ)，來降解靶mRNA或抑制靶mRNA的翻譯。最終通過下調(diào)靶基因的蛋白生成調(diào)控生物的發(fā)育、細(xì)胞的增殖凋亡及腫瘤的發(fā)生發(fā)展。

在腫瘤發(fā)病過程中，miRNA的表達(dá)是下調(diào)還是上調(diào)取決于它的靶基因是腫瘤抑制基因還是癌基因，一種腫瘤抑制作用的miRNA表達(dá)下調(diào)可能促進(jìn)靶癌基因的表達(dá)大大增加，而一種誘發(fā)腫瘤發(fā)生的miRNA表達(dá)上調(diào)可能導(dǎo)致靶腫瘤抑制基因的表達(dá)降低，最終導(dǎo)致腫瘤形成。

2 miRNA相關(guān)的研究方法

miRNA相關(guān)的研究方法包括以下3個步驟：miRNA的分離純化，miRNA表達(dá)水平的檢測，靶基因的預(yù)測。不同的樣本采取不同的分離純化的方法，細(xì)胞和組織中多采取mirVanaTMmiRNA Isolation Kit試劑盒進(jìn)行；待miRNA分離純化后，應(yīng)用Northern Blot、Microarrays和實(shí)時定量聚合酶鏈反應(yīng)(polymerase chain reaction，PCR)檢測miRNA的表達(dá)水平，其中實(shí)時定量PCR具有高敏感性、高特異性的特點(diǎn)；TaqMan?MicroRNA Assays和MegaplexTMRT Primers/Primer Pools同時可進(jìn)行miRNA表達(dá)譜分析；而后再應(yīng)用TargetScan、miRanda、DIANA2MicroT、PicTar、StarBase、miRDB等軟件推測靶基因。

3 膀胱癌相關(guān)miRNA表達(dá)情況

膀胱癌中基因突變、表觀遺傳學(xué)改變等導(dǎo)致相應(yīng)的miRNA 表達(dá)異常。隨著miRNA檢測技術(shù)發(fā)展，膀胱癌組織或細(xì)胞株以及膀胱癌患者體液中越來越多表達(dá)異常的miRNA 被發(fā)現(xiàn)。

3.1 膀胱癌組織或膀胱癌細(xì)胞株中miRNA表達(dá)情況 Catto等[1]在2009年對6種膀胱癌細(xì)胞株、20個正常膀胱組織、52個膀胱癌組織中的miRNA表達(dá)進(jìn)行研究。膀胱癌組織中有16種異常表達(dá)的miRNA；并應(yīng)用Target-Scan推測miR-99a、miR-100、miR-214、miR-145、miR-30a、miR-125b、miR-507的作用靶點(diǎn)是成纖維細(xì)胞生長因子受體3，miR-218的作用靶點(diǎn)為H-Ras。Chen等[2]應(yīng)用Solexa測序技術(shù)發(fā)現(xiàn)與正常膀胱組織相比，膀胱癌組織中33種miRNA表達(dá)上調(diào)，41種miRNA表達(dá)下調(diào)；其中miR-96上調(diào)最明顯，miR-490-5p下調(diào)最明顯。夏偉等[3]利用miRNA芯片技術(shù)在膀胱癌和癌旁組織中發(fā)現(xiàn)差異有統(tǒng)計(jì)學(xué)意義的miRNA共115種，其中上調(diào)的73種、下調(diào)的42種。下調(diào)的有miR-145、miR-143、miR-133a/b、miR-125b、miR-99a等，上調(diào)的有miR-708、miR-200b/c、miR-205、miR-182、miR-21等。與膀胱癌相關(guān)的miRNA異常表達(dá)情況及作用靶點(diǎn)見表1。

表1 膀胱癌組織及細(xì)胞株中miRNA異常表達(dá)情況

caspase-2：人胱天冬蛋白酶2；RhoC:RhoC蛋白；VEGFC：血管內(nèi)皮生長因子C；MAP4K1：造血祖細(xì)胞激酶1；IRS1:人胰島素受體底物1；FOXO-1:轉(zhuǎn)錄因子；REG/BCLAF1:BCL相關(guān)轉(zhuǎn)錄因子；PI3K-AKT:磷脂酰肌醇3激酶-蛋白激酶B信號轉(zhuǎn)導(dǎo)通路;TAGLN2:細(xì)胞骨架相關(guān)蛋白2；LASP1：肌動蛋白支架蛋白1；GSTP1:人谷胱甘肽S轉(zhuǎn)移酶P1；mTOR:雷帕霉素靶蛋白；FGFR3：成纖維細(xì)胞生長因子受體3；FSCNI：FSCNI 基因；Mucin-4：黏蛋白-4；EZH2：EZH2 基因；ERK5：細(xì)胞外信號調(diào)節(jié)激酶5；RAS：RAS基因；Socs7：細(xì)胞因子信號轉(zhuǎn)導(dǎo)抑制因子7；C-met：酪氨酸激酶受體；HMGA1：正高遷移率族蛋白A1家族；CDK4:周期蛋白依賴性激酶4

3.2 miRNA在膀胱癌患者體液中的表達(dá)情況 膀胱癌組織及膀胱癌細(xì)胞株中miRNA研究主要意義在于miRNA在膀胱癌的發(fā)生、發(fā)展中作用，而miRNA在膀胱癌患者體液中的表達(dá)情況研究則重在miRNA在膀胱癌診治中的意義，更易于應(yīng)用到臨床膀胱癌的診治工作。

3.2.1 miRNA在膀胱癌患者尿液中表達(dá)情況 Mengual等[25]對181例膀胱腫瘤患者及136例對照組的尿沉渣分析，發(fā)現(xiàn)膀胱癌患者尿液中40種異常表達(dá)的miRNA，其中27種下調(diào)、13種上調(diào)；與低級別組相比，高級別組中有30種異常表達(dá)的miRNA，其中20種下調(diào)、10種上調(diào)；Miah等[26]在膀胱癌患者尿液中發(fā)現(xiàn)9種異常的miRNA(miR-15a、miR24-1、miR27b、miR100、miR135b、miR203、miR212、miR328、miR1224)，并提出miRs-135b、miR15b、miR1224-3p三種共同診斷膀胱癌可達(dá)94.1%的靈敏度及86%的特異度。

Wang等[27]對51例膀胱癌患者及24例健康對照的尿沉渣及尿上清液研究發(fā)現(xiàn)，與對照組相比，膀胱癌患者尿沉渣中miR-200家族、miR-192和miR-155低表達(dá)，尿上清液中miR-192 低表達(dá)，miR-155高表達(dá)；miR-200c和miR-141在術(shù)后的尿沉渣恢復(fù)正常。Mlcochova等[28]研究發(fā)現(xiàn)，miR-126、miR-200家族和miR-183家族(包括miR-182、miR-183和miR-96)在尿中表達(dá)上調(diào)。Kim等[29]發(fā)現(xiàn)miR-214在膀胱癌患者尿中明顯升高，可作為非肌層浸潤性膀胱癌的診斷靶點(diǎn)。尿液中膀胱癌相關(guān)的miRNA異常表達(dá)情況見表2。

3.2.2 miRNA在膀胱癌患者血液中表達(dá)情況 Adam等[34]檢測20個膀胱癌患者及18個非腫瘤患者的血漿miRNA表達(dá)情況。發(fā)現(xiàn)40種具有診斷意義的miRNAs，如miR-541、

表2 膀胱癌患者尿液中miRNA異常表達(dá)情況

miR-200b、miR-566、miR-487和miR-148b表達(dá)上調(diào)，而miR-25、 miR-92a、miR-92b、miR-302和miR-33b表達(dá)下調(diào)；而且指出miR-92和miR-33與臨床分期有關(guān)。并應(yīng)用Logistic回歸模型推測確診膀胱腫瘤可達(dá)89%的準(zhǔn)確度，92%的靈敏度將浸潤組與其他病例鑒別出來，100%靈敏度鑒別肌層浸潤性與對照組，79%靈敏度區(qū)分肌層浸潤性、非肌層浸潤性和對照組。

4 miRNA在膀胱癌臨床應(yīng)用中的研究

4.1 miRNA與膀胱癌的診斷 膀胱癌組織及膀胱癌細(xì)胞株中異常表達(dá)的miRNA及膀胱癌患者體液中異常表達(dá)的miRNA 均可以用于膀胱癌的診斷，血液及尿液中異常表達(dá)的miRNA在膀胱癌的診斷中更有實(shí)際應(yīng)用價值，可以為膀胱癌的早期臨床診斷提供依據(jù)。Catto等[1]推測膀胱癌組織中miR-526b、miR-507、miR-147、miR-517a、miR-556診斷膀胱癌的靈敏度為90%～100%，特異度為80%～100%，證明這些miRNA可作為膀胱癌的診斷靶點(diǎn)；Mengual等[25]提出尿液中6種miRNAs(miR-187、miR-18a*、miR-25、miR-142-3p、miR-140-5p、miR-204)診斷出膀胱癌的靈敏度和特異度分別為84.8%和86.5%，miR-92a和miR-125b鑒別低級別組和高級別組的靈敏度和特異度分別為84.94%和74.14%。

4.2 miRNA與膀胱癌的病理分級分期 Pignot等[35]對11個正常膀胱樣本及166個腫瘤樣本研究發(fā)現(xiàn)15種miRNA 在膀胱癌組織中異常表達(dá)，其中miR-146b和miR-9在肌層浸潤組表達(dá)顯著上調(diào)，其余13種miRNA在腫瘤樣本中均表達(dá)異常，3種miRNAs表達(dá)上調(diào)(miR-200b、miR-182、miR-138)，10種 miRNA下調(diào)(miR-1、miR-133a、miR-133b、miR-145、miR-143、miR-204、miR-921、miR-1281、miR-199a和miR-199b)，并發(fā)現(xiàn)miR-9、miR-182和miR-200b與浸潤性膀胱癌的浸潤性有關(guān)。Xie等[36]對28例浸潤性膀胱癌樣本及11例非浸潤性膀胱癌樣本進(jìn)行分析，發(fā)現(xiàn)浸潤組有7種異常表達(dá)的miRNA：miR-29c、miR-200a、miR-378、miR-429、miR-200c和miR-141上調(diào)，miR-451下調(diào)，這些miRNA可能與腫瘤的浸潤性有關(guān)。

4.3 miRNA與膀胱癌的治療 針對miRNA在膀胱癌治療中的研究，主要通過沉默膀胱癌細(xì)胞株中表達(dá)上調(diào)的miRNA和轉(zhuǎn)染下調(diào)的miRNA來控制異常表達(dá)的miRNA，并觀察膀胱癌細(xì)胞株的增殖、活性、凋亡及耐藥性，從而明確其在治療中作用。Kozinn等[16]研究發(fā)現(xiàn)，let-7b、let-7i、miR-1290和miR-138與膀胱癌細(xì)胞株吉西他濱耐藥有關(guān)；并證明通過改變let-7b、let-7i、miR-1290和miR-138這些miRNA表達(dá)可提高吉西他濱對膀胱癌的治療效果。Nordentoft 等[37]研究發(fā)現(xiàn)，通過減少miR-138，增加miR-27a和miR-642可增加細(xì)胞株對順鉑的敏感性。Tao 等[10]發(fā)現(xiàn)，miR-21在尿路上皮癌組織高表達(dá)，并可能通過磷脂酰肌醇3激酶/ 蛋白激酶B通路促進(jìn)癌細(xì)胞增殖和T24細(xì)胞株的抗化學(xué)作用，調(diào)節(jié)膀胱癌對阿霉素的敏感性。

4.4 miRNA與膀胱癌病情進(jìn)展及預(yù)后 miRNA不但與膀胱癌的發(fā)生有關(guān)，miRNA的表達(dá)情況也可以預(yù)測膀胱癌患者的病情進(jìn)展及預(yù)后，準(zhǔn)確評估患者病情及進(jìn)展情況指導(dǎo)治療。

Pignot 等[35]發(fā)現(xiàn)miR-9、miR-182和miR-200b與肌層浸潤性膀胱癌的浸潤性、無復(fù)發(fā)生存率、總生存期有關(guān)。Zaravinos等[38]研究發(fā)現(xiàn)高水平miR-21與表達(dá)較差的總生存期有關(guān)，并提出miR-21、miR-210和miR-378可作為總生存期的獨(dú)立預(yù)后因素，miR-21和miR-378可作為復(fù)發(fā)的獨(dú)立預(yù)后因素。Rosenberg等[39]對進(jìn)展組和非進(jìn)展組的miRNA表達(dá)譜分析，發(fā)現(xiàn)17種miRNA差異有統(tǒng)計(jì)學(xué)意義，尤其是miR-182、miR-29c*、miR-130a和miR-31。miR-29c*在進(jìn)展組中明顯低表達(dá)，可能被用于鑒別膀胱癌T1期中高危組和低危組，并指出miR-29c*的高水平表達(dá)與良好預(yù)后有關(guān)，從而證明膀胱癌的進(jìn)展與miRNA水平的改變有關(guān)。

5 結(jié) 語

膀胱癌的發(fā)生發(fā)展、膀胱癌細(xì)胞的侵襲遷移、藥物敏感性與miRNA密切相關(guān)。不僅膀胱癌組織、膀胱癌細(xì)胞株中miRNA表達(dá)異常，而且在膀胱癌患者的如血液、尿液等體液中也能檢測出異常表達(dá)的miRNA，這些研究結(jié)果讓研究者們對miRNA在膀胱癌診斷、病理分期分級、治療、病理進(jìn)展及預(yù)后等作用有了初步的認(rèn)識，這些研究也為膀胱癌病因及臨床診治提供了一個新的方向，但是如何將miRNA應(yīng)用于膀胱癌的早期診斷、基因靶向治療和預(yù)后評估需要更深一步研究。參考文獻(xiàn)

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Research Progress on MicroRNA in the Incidence and Development of Bladder Cancer

LIYue-xi1,LUHong-yan2,SONGDong-kui2.

(1.DepartmentofNeurosurgery,HuaiheHospitalofHenanUniversity，Kaifeng475000,China; 2.theFifthWardinDepartmentofUrology,theFirstAffiliatedHospitalofZhengzhouUniversity,Zhengzhou450052,China)

The incidence and development of bladder cancer is closely associated with the abnormal expression of different microRNA(miRNA),so miRNA can be potential biological targets in the diagnosis and treatment of bladder cancer.In recent years,the targets and molecular mechanisms of miRNA associated with bladder cancer have been constantly discovered,which makes us understand miRNA′s role in the incidence and development of bladder cancer,while studies of miRNA in urine and blood also provide basis for the early diagnosis of bladder cancer.Further studies of miRNA and bladder cancer will provide new directions for early diagnosis,gene-targeted therapy,and prognosis assessment of bladder cancer.

Bladder cancer; microRNA; Biological targets

R737.1

A

1006-2084(2015)12-2171-04

10.3969/j.issn.1006-2084.2015.12.022

2014-04-15

2014-10-29 編輯：相丹峰