崔曼莉,周蘇娜,張明鑫,王景杰(第四軍醫(yī)大學唐都醫(yī)院:消化內(nèi)科,放療科,陜西西安70038)
miRNAs在食管鱗癌中的功能、機制及治療前景
崔曼莉1,周蘇娜2,張明鑫1,王景杰1(第四軍醫(yī)大學唐都醫(yī)院:1消化內(nèi)科,2放療科,陜西西安710038)
目的:食管鱗癌(ESCC)在東亞地區(qū)占主要地位,大約一半的ESCC病例發(fā)生在中國.雖然食管鱗癌的診斷和治療取得了較大的進步,但預后仍不理想,其精確調(diào)控機制仍有待于進一步研究和探索.MicroRNAs(miRNAs)是一組能夠在轉(zhuǎn)錄后水平調(diào)控基因表達的非編碼小RNA,不同的腫瘤類型和致癌途徑中,miRNAs表達失調(diào)控,呈現(xiàn)出表達上調(diào)、下調(diào)或缺失,顯現(xiàn)出類似于癌基因或抑癌基因的功能.本研究綜述了miRNAs在ESCC中的表達、功能、機制及治療前景的相關進展.
功能;機制;治療前景;miRNAs;食管鱗癌
食管癌(esophageal cancer,EC)是全球常見八大惡性腫瘤之一,其死亡率居于全球相關腫瘤的第六位.雖然食管腺癌(esophageal adenocarcinoma,EAC)在西方國家因發(fā)病率逐年升高而備受關注,但食管鱗癌(esophageal squamous cell carcinoma,ESCC)在東亞地區(qū)仍占主要地位,大約一半的ESCC病例發(fā)生在中國[1-2].雖然近三十年來ESCC的診斷和治療取得了較大的進步,但預后仍不理想,5年生存率僅為15%~25%[3].近年來,大量研究[4]發(fā)現(xiàn)了一系列ESCC相關的基因異常,如p53、p21、Cyclin D1等,但其精確調(diào)控機制仍有待進一步研究和探索.
MicroRNAs(miRNAs)是一組能夠在轉(zhuǎn)錄后水平調(diào)控基因表達的非編碼小RNA,在一系列病理生理過程中發(fā)揮著重要的作用.近來的研究發(fā)現(xiàn),不同的腫瘤類型和致癌途徑中,miRNAs表達失調(diào),呈現(xiàn)出表達上調(diào)、下調(diào)或缺失,顯現(xiàn)出類似于癌基因或抑癌基因的功能.進一步的研究提示,miRNAs還能夠作為腫瘤顯像、診斷、治療以及預后的生物標記.由于西方食管癌以EAC為主,故早期的食管癌miRNAs文獻主要集中在EAC,ESCC尤其是我國西部高發(fā)地區(qū)的相關數(shù)據(jù)不多.雖然國外已有相關綜述探討了miRNAs在EC中的作用及研究進展,但多數(shù)均局限于EAC.近年來,包括我們課題組在內(nèi)的國內(nèi)學者逐漸重視ESCC與miRNAs的關系,發(fā)表了一系列文章.本研究對近年miRNAs與ESCC研究的相關進展進行綜述,現(xiàn)報道如下.
miRNAs是一類長度介于(18~25)nt的單鏈RNA,其本身不具有開放閱讀框(ORF),不編碼任何蛋白質(zhì),成熟miRNA的5'端帶有磷酸基團(-HPO4),3'端帶有羥基(-OH).miRNAs由基因組編碼,并由RNA聚合酶II轉(zhuǎn)錄為長的轉(zhuǎn)錄本,即初始miRNAs(pri-miRNAs),一般長為幾千個堿基大小.成熟的miRNAs便由pri-miRNAs通過下述步驟生成:通過在細胞核中的RNase-III酶Drosha以及其結(jié)合伴侶DGCR8組成的復合體識別,將pri-miRNAs處理成含成熟miRNAs的60~80個核苷酸的前體miRNAs(pre-miRNAs).pre-miRNAs很快由核輸出因子Exportin-5識別并協(xié)同Ran-GTP被運送至細胞漿,之后被另外一個RNA聚合酶III Dicer識別并切割為長18~24個核苷酸長度的雙鏈.其中的一條鏈被稱為引導鏈,將雙鏈引導至含Argonaute蛋白的RISC復合體中,使其中僅一條鏈和RNA誘導的沉默復合物(RNA-induced silencing complex,RISC)穩(wěn)定結(jié)合,從而成為成熟miRNAs.miRNAs引導RISC復合物結(jié)合靶mRNA的3’-UTR的結(jié)合序列,從而將之清除或進行轉(zhuǎn)錄后抑制[5-7].
截止2014年6月,miRBase最新21.0版正式發(fā)布,新版數(shù)據(jù)庫收錄miRNAs總數(shù)量已突破35000條,相比上一版本(20.0版)增長近20%,新增4196條發(fā)夾前體序列和5441條成熟體miRNAs.miRNAs主要是通過抑制它的靶基因而發(fā)揮調(diào)控作用,至今尚未發(fā)現(xiàn)有上調(diào)能力的miRNAs,其在發(fā)育、細胞增殖、凋亡、脂類代謝、激素分泌及腫瘤發(fā)生等多種生理和病理過程中發(fā)揮重要作用.本研究主要關注miRNAs在ESCC中的表達、功能、機制及治療前景.
2.1 ESCC的miRNAs表達譜通過ESCC及癌旁或者中間過程(如炎癥、不典型增生等)的miRNAs表達譜的變化,明確上調(diào)或下調(diào)的miRNAs,對于進行進一步的功能研究意義重大.Guo等[8]應用芯片技術探討了我國ESCC中miRNAs的表達譜情況,首先采用31例配對的ESCC及癌旁組織進行芯片檢測,篩選出差異表達的miRNAs,設計檢測模型;再應用24例配對資料和1例非配對資料進行驗證,最后應用22例含完整預后信息的組織進行預后分析,得出miR-103/107的高表達是不良預后的獨立風險因子.Feber等[9]應用芯片技術研究了美國ESCC的表達變化,發(fā)現(xiàn)miR-21的高表達,以及miR-203與miR-205的低表達.Mathé等[10]利用收集的美國和日本的ESCC患者的組織,發(fā)現(xiàn)癌旁中miR-21的高表達與不良預后密切相關.Ogawa[11]則應用實時定量熒光PCR技術檢測了鱗癌組織中73種miRNAs的表達變化,發(fā)現(xiàn)了與臨床病理相關連的miRNAs,且證實miR-129的高表達是預后不良的獨立風險因子.Lee等[12]在研究miR-373的功能時對5例ESCC的表達譜進行分析,發(fā)現(xiàn)let-7d、miR-330、miR-340以及miR-373高表達.有研究報道應用含較新miRNAs數(shù)據(jù)庫版本的芯片,獲得了我國ESCC的表達譜[13-15].這些基于組織的表達譜變化,既有重疊(如miR-21的上調(diào)和miR-203下調(diào)),也有不同,其根本原因是標本的病理特征存在差異,同時還有腫瘤間質(zhì)細胞的干擾.因此,Zhu等[16]應用激光捕獲顯微切割技術選取組織中的正常、變異及腫瘤細胞進行ESCC表達譜研究,發(fā)現(xiàn)了miR-21、miR-25、miR-106b的高表達以及miR-145和miR-203的低表達,為ESCC組織表達譜研究提供了新的思路.
由于細胞株更容易獲得并進行相關的處理,之后,學術界又開始探討ESCC細胞株中miRNAs表達譜.鄭志范等[17]對比了放療抵抗株的KYSE-150R和親本細胞的miRNAs表達譜的差異,并應用生物信息學尋找可能的靶基因,為探討ESCC的放療耐受機制提供了參考.Kimura等[18]通過對比8種ESCC細胞株和正常食管粘膜上皮細胞株之間miRNAs表達譜的差異,證實miR-205和miR-21是ESCC的特異性標志.具體的細節(jié)及參數(shù)請參照表1.
miRNAs檢測技術的不斷進步及人們對miRNAs生物學行為認識的不斷增加,使得ESCC患者循環(huán)miRNAs表達譜在診斷中的價值也逐漸受到重視,一些具有診斷或預后價值的循環(huán)miRNAs[19-20]被發(fā)現(xiàn).Liu等[21]新近發(fā)表的一篇薈萃分析總結(jié)了已發(fā)表的ESCC中的循環(huán)miRNAs研究,發(fā)現(xiàn)其在ESCC中的敏感性、特異性、陽性似然比、陰性似然比和診斷優(yōu)勢比分別為79.9%、81.3%、4.27、0.25和17.29,提示其可作為早期診斷ESCC的潛在標志物,但仍需大量患者數(shù)據(jù)來驗證.
2.2 ESCC中miRNAs的功能如前所述,miRNAs能夠在轉(zhuǎn)錄后水平調(diào)控基因的表達,根據(jù)表達譜中其表達水平的變化以及其對癌基因或抑癌基因的表達調(diào)控,便可以確定ESCC中miRNAs的可能功能.因此,揭示ESCC中miRNAs功能的方法有很多.以具有癌基因功能的miRNAs為例,一種是在表達譜的基礎之上,將具有顯著性的高表達的miRNAs作為候選的具有癌基因功能的miRNAs,通過構建其表達質(zhì)粒和設計抑制劑,探討其分別在過表達和抑制表達的情況下對ESCC生物學行為的影響,從而判定功能,進一步在生物信息學基礎之上尋找可能的靶標,應用報告基因,明確其可信的調(diào)控機制;另外一種為通過已知抑癌基因,通過生物信息學反查可能的miRNAs,再通過過表達和抑制觀察其生物學功能;此外,針對特殊miRNAs,應用生物信息學方法尋找可能的靶標,文獻檢索可能的靶標的功能,再重復實驗,明確功能;還可以選取其他腫瘤中已經(jīng)證實的具有抑癌基因功能的miRNAs,探討其在ESCC中是否仍發(fā)揮相似的功能和調(diào)控相同的靶標.
表1 ESCC的miRNAs表達譜研究一覽
(1)具有癌基因功能的miRNAs
研究最多且結(jié)果最為一致的類癌基因的miRNAs是miR-21.Mori、Hiyoshi和Ma的團隊都證實了miR-21在ESCC中的癌基因功能,相關的靶標分別是程序性細胞凋亡因子4(programmed cell death 4,PDCD4)和PTEN等,進而影響ERK信號通路等,促進腫瘤細胞的增殖和侵襲,參與了ESCC的發(fā)生及發(fā)展[22-26],miR-21也成為ESCC治療的潛在靶點[27].此外,miR-373、miR-92a、miR-25、miR-10b、miR-130b、miR-1290、miR-330-3p、miR-224都與增殖或侵襲轉(zhuǎn)移相關,靶標參見表2[12,28-36].
結(jié)合ESCC的診治現(xiàn)狀,越來越多的研究開始關注治療耐受與抵抗的困境,雖然已有的研究發(fā)現(xiàn)了大量與耐藥相關的基因,但是有關的精確調(diào)控機制仍未了解,miRNAs的研究為耐藥的調(diào)控提供了新的視野和思路.多藥耐藥基因1(multidrug resistance gene 1,MDR1)及蛋白是誘發(fā)腫瘤細胞耐藥的重要原因,miR-296和miR-27a被證實能夠調(diào)控MDR1從而參與耐藥,同時也與ESCC增殖、凋亡對抗相關[37-38];Imanaka等[39]報道高表達miR-141能夠通過調(diào)控Yes相關蛋白1(Yes-associated protein 1,YAP1)的表達使ESCC細胞株耐受順鉑誘導的凋亡;Hamano[41]則發(fā)現(xiàn)miR-200c在ESCC耐藥中的作用與Akt信號通路的激活相關,其靶標為protein phosphatase 2(formerly2A),regulatorysubunitA,betaisoform(PPP2R1B)[40];miR-483-3p則通過靶向EI24與增殖、細胞周期、侵襲以及耐藥均有關系(表2).
表2 ESCC中具有癌基因功能的miRNAs
(2)具有抑癌基因功能的miRNAs
相較于具有癌基因功能的miRNAs,更多在ESCC中具有抑癌基因功能的miRNAs被鑒定出來(表3)[42-94].大部分miRNAs都通過靶向特定的靶基因發(fā)揮抑制增殖和侵襲轉(zhuǎn)移的功能,從而發(fā)揮抑癌基因功能.Kano等[42]研究發(fā)現(xiàn)三種具有抑癌基因功能的miRNAs,包含miR-145、miR-133a和miR-133b,可共同調(diào)控actin-binding protein,F(xiàn)ascin homolog 1(FSCN1)的表達,參與對ESCC的增殖和侵襲的抑制.miR-29c、miR-200b、miR-577、miR-1、miR-495和miR-181d可通過調(diào)控cyclin E、CDK2、TSGA10、cyclin D1,CDK4、Akt1、DERL1細胞周期相關的靶基因調(diào)控細胞周期.miR-145、miR-133a、miR-143和miR-200b可通過靶向眾多靶基因參與調(diào)控EMT從而抑制腫瘤的遷移、侵襲和轉(zhuǎn)移,miR-375和miR-29b則直接通過靶向基質(zhì)金屬蛋白酶(matrix metalloproteinases,MMPs)如MMP13和MMP2抑制侵襲.本研究也持續(xù)關注miRNAs在ESCC中的作用:明確了miR-518b、miR-302b和miR-520a通過調(diào)控Rap1、CXCR4,IRF2和ERBB4發(fā)揮抑癌基因功能,影響ESCC的增殖、凋亡和侵襲能力.更重要的是,miR-302b可通過靶向多個靶基因調(diào)控ESCC腫瘤相關性炎癥(cancer related inflammation,CRI)信號通路.我們還明確了miR-381與ESCC的放療敏感顯著相關,潛在的靶基因包括XIAP、CDK1、LEF1、CTNNB1,放療是ESCC治療的重要方式,提高放療敏感性意義重大,除了miR-381外,其他課題組報道了miR-22和miR-98也可以增加放療敏感性,可能的靶基因包括Rad51和BCL2;而miR-218則可以通過靶向BMI1發(fā)揮化療增敏的作用,miR-100的下游靶基因是mTOR,而mTOR信號途徑在包括ESCC在內(nèi)的多種腫瘤中介導耐藥[95],因此我們推測miR-100也可能具有治療增敏的功能,值得進一步研究.
相較于其他腫瘤類型,現(xiàn)有的有關ESCC中miRNAs功能研究的相關報道并不多見,主要受限于以下幾個方面的原因.第一,受限于ESCC的地理分布.歐美研究的重點是EAC及Barrett食管[96-97],因為miRNAs作為新近發(fā)現(xiàn)的調(diào)控因子,進行相關研究的科研經(jīng)費較大,實驗技術要求較高,限制了其快速發(fā)展.但是隨著miRNAs相關實驗技術的不斷發(fā)展和我國科研實力的不斷增強,ESCC與miRNAs的相關研究的報道也不斷增加,以“microRNAs”和“esophageal squamous cell carcinoma”作為關鍵詞在PubMed上進行搜索,僅有259篇文獻,且大多為我國科研人員的文章;第二,更為重要的是miRNAs研究本身存在的問題.miRNAs本身的產(chǎn)生機制及調(diào)控機制仍未完全揭示,存在很多未知之處,尤其是其對靶基因的調(diào)控機制及算法上仍存在爭議;其次,因為單個miRNAs可以調(diào)控多個基因的表達,而單個基因也同時受多個miRNAs的調(diào)控,而現(xiàn)行的研究結(jié)果都是在單一調(diào)控因素的基礎上得出的,其準確性有待進一步考證.而該問題受我們所處時代的研究方法及思路的限制,即缺乏高通量的研究模式或叫做整體研究的思路,即便如此,現(xiàn)有的數(shù)據(jù)也已為ESCC的預防、診斷、治療以及預后提供了一定的依據(jù).
表3 ESCC中具有抑癌基因功能的miRNAs
既然miRNAs在ESCC中表達失調(diào)控,且發(fā)揮抑癌基因或癌基因功能,那是否可以應用于ESCC的治療呢?很遺憾,在ESCC中未見相關報道,但其他腫瘤中的一些研究則具有提示意義.在標準治療失敗的惡性胸膜間皮瘤和晚期非小細胞肺癌患者中,開展了一項應用miR-15/16類似物治療的臨床Ⅰ期研究,將miR-16類似物與EGFR抗體偶聯(lián),并應用納米細胞EDV(EngeneIC delivery vehicle)包裝后靜脈注射,TAT2015大會的摘要數(shù)據(jù)顯示,5例進行試驗的患者耐受良好,僅顯示出一過性的細胞因子相關的副反應,更多的結(jié)果有待進一步觀察[98].當然,miRNAs應用于治療還有一段很長的路要走,現(xiàn)階段需要克服的問題主要包括:優(yōu)化配送系統(tǒng)、改進miRNAs的穩(wěn)定性、了解miRNAs療法的脫靶效應等,才可以使miRNAs的治療實踐從實驗室過渡到臨床應用[99].也期待開展miRNAs應用于ESCC治療的臨床研究,這也依賴于對miRNAs本身生理過程的明晰和呼喚更多更基礎的研究證據(jù).
綜合以上所述,miRNAs在ESCC中表達失調(diào)控,并通過多種靶基因發(fā)揮抑癌基因或癌基因功能,其臨床應用的潛在價值已被充分證實,雖然缺乏應用研究工作,但我國學者的相關研究也取得了一定的進展.相較于其他腫瘤,miRNAs在ESCC中仍處在起始階段,結(jié)合其他腫瘤的相關研究,仍待進一步的發(fā)掘.隨著miRNAs研究的不斷深入、ESCC發(fā)病機制的不斷明確及相關分子生物技術的不斷革新,相信在不久的將來,miRNAs無論是作為診斷或判斷預后的標志物,還是作為治療的靶點,必將更好的服務于ESCC的診斷及治療.
[1]Torre LA,Bray F,Siegel RL,et al.Global cancer statistics,2012[J].CA Cancer J Clin,2015,65(2):87-108.
[2]Chen W,Zheng R,Baade PD,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,66(2):115-132.
[3]Domper Arnal MJ,F(xiàn)errández Arenas á,Lanas Arbeloa á.Esophageal cancer:Risk factors,screening and endoscopic treatment in Western and Eastern countries[J].World J Gastroenterol,2015,21(26):7933-7943.
[4]Tétreault MP.Esophageal Cancer:Insights From Mouse Models[J].Cancer Growth Metastasis,2015,8(Suppl 1):37-46.
[5]Li Z,Rana TM.Therapeutic targeting of microRNAs:current status and future challenges[J].Nat Rev Drug Discov,2014,13(8): 622-638.
[6]Calin GA,Sevignani C,Dumitru CD,et al.Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers[J].Proc Natl Acad Sci U S A,2004,101(9): 2999-3004.
[7]Hayes J,Peruzzi PP,Lawler S.MicroRNAs in cancer:biomarkers, functions and therapy[J].Trends Mol Med,2014,20(8):460-469.
[8]Guo Y,Chen Z,Zhang L,et al.Distinctive microRNA profiles relating to patient survival in esophageal squamous cell carcinoma[J].Cancer Res,2008,68(1):26-33.
[9]Feber A,Xi L,Luketich JD,et al.MicroRNA expression profiles of esophageal cancer[J].J Thorac Cardiovasc Surg,2008,135(2): 255-260.
[10]Mathé EA,Nguyen GH,Bowman ED,et al.MicroRNA expression in squamous cell carcinoma and adenocarcinoma of the esophagus: associations with survival[J].Clin Cancer Res,2009,15(19): 6192-6200.
[11]Ogawa R,Ishiguro H,Kuwabara Y,et al.Expression profiling of micro-RNAs in human esophageal squamous cell carcinoma using RT-PCR[J].Med Mol Morphol,2009,42(2):102-129.
[12]Lee KH,Goan YG,Hsiao M,et al.MicroRNA-373(miR-373)post-transcriptionally regulates large tumor suppressor,homolog 2(LATS2)and stimulates proliferation in human esophageal cancer[J].Exp Cell Res,2009,315(15):2529-2538.
[13]Wu BL,Xu LY,Du ZP,et al.MiRNA profile in esophageal squamous cell carcinoma:downregulation of miR-143 and miR-145[J].World J Gastroenterol,2011,17(1):79-88.
[14]Hong L,Han Y,Zhang H,et al.The prognostic and chemotherapeutic value of miR-296 in esophageal squamous cell carcinoma[J].Ann Surg,2010,251(6):1056-1063.
[15]Zang W,Wang Y,Du Y,et al.Differential expression profiling of microRNAs and their potential involvement in esophageal squamous cell carcinoma[J].Tumour Biol,2014,35(4):3295-3304.
[16]Zhu L,Yan W,Rodriguez-Canales J,et al.MicroRNA analysis of microdissected normal squamous esophageal epithelium and tumor cells[J].Am J Cancer Res,2011,1(5):574-584.
[17]鄭志范,蘇華芳,鄒 燕,等.microRNA在食管癌放射抵抗細胞表達譜研究[J].中華醫(yī)學雜志,2011,91(9):639-642.
[18]Kimura S,Naganuma S,Susuki D,et al.Expression of microRNAs in squamous cell carcinoma of human head and neck and the esophagus:miR-205 and miR-21 are specific markers for HNSCC and ESCC[J].Oncol Rep,2010,23(6):1625-1633.
[19]Zhang C,Wang C,Chen X,et al.Expression profile of microRNAs in serum:a fingerprint for esophageal squamous cell carcinoma[J].Clin Chem,2010,56(12):1871-1879.
[20]Takeshita N,Hoshino I,Mori M,et al.Serum microRNA expression profile:miR-1246 as a novel diagnostic and prognostic biomarker for oesophageal squamous cell carcinoma[J].Br J Cancer,2013,108(3):644-652.
[21]Liu F,Tian T,Xia LL,et al.Circulating miRNAs as novel potential biomarkers for esophageal squamous cell carcinoma diagnosis:a meta-analysis update[J].Dis Esophagus,2016.
[22]Mori Y,Ishiguro H,Kuwabara Y,et al.MicroRNA-21 induces cell proliferation and invasion in esophageal squamous cell carcinoma[J].Mol Med Rep,2009,2(2):235-239.
[23]Hiyoshi Y,Kamohara H,Karashima R,et al.MicroRNA-21 regu-lates the proliferation and invasion in esophageal squamous cell carcinoma[J].Clin Cancer Res,2009,15(6):1915-1922.
[24]Ma WJ,Lv GD,Tuersun A,et al.Role of microRNA-21 and effect on PTEN in Kazakh's esophageal squamous cell carcinoma[J].Mol Biol Rep,2011,38(5):3253-3260.
[25]Liu T,Liu Q,Zheng S,et al.MicroRNA-21 promotes cell growth and migration by targeting programmed cell death 4 gene in Kazakh's esophageal squamous cell carcinoma[J].Dis Markers,2014:232837.
[26]Liu F,Zheng S,Liu T,et al.MicroRNA-21 promotes the proliferation and inhibits apoptosis in Eca109 via activating ERK1/2/MAPK pathway[J].Mol Cell Biochem,2013,381(1-2):115-125.
[27]Huang S,Li XQ,Chen X,et al.Inhibition of microRNA-21 increases radiosensitivity of esophageal cancer cells through phosphatase and tensin homolog deleted on chromosome 10 activation[J].Dis Esophagus,2013,26(8):823-831.
[28]Liu W,Li M,Chen X,et al.MicroRNA-373 promotes migration and invasion in human esophageal squamous cell carcinoma by inhibiting TIMP3 expression[J].Am J Cancer Res,2015,6(1):1-14.
[29]Chen ZL,Zhao XH,Wang JW,et al.microRNA-92a promotes lymph node metastasis of human esophageal squamous cell carcinoma via E-cadherin[J].J Biol Chem,2011,286(12):10725-10734.
[30]Xu X,Chen Z,Zhao X,et al.MicroRNA-25 promotes cell migration and invasion in esophageal squamous cell carcinoma[J].Biochem Biophys Res Commun,2012,421(4):640-645.
[31]Tian Y,Luo A,Cai Y,et al.MicroRNA-10b promotes migration and invasion through KLF4 in human esophageal cancer cell lines[J].J Biol Chem,2010,285(11):7986-7894.
[32]Yu T,Cao R,Li S,et al.MiR-130b plays an oncogenic role by repressing PTEN expression in esophageal squamous cell carcinoma cells[J].BMC Cancer,2015,15:29.
[33]Li M,He XY,Zhang ZM,et al.MicroRNA-1290 promotes esophageal squamous cell carcinoma cell proliferation and metastasis[J].World J Gastroenterol,2015,21(11):3245-3255.
[34]Mao Y,Liu J,Zhang D,et al.MiR-1290 promotes cancer progression by targeting nuclear factor I/X(NFIX)in esophageal squamous cell carcinoma(ESCC)[J].Biomed Pharmacother,2015,76: 82-93.
[35]Meng H,Wang K,Chen X,et al.MicroRNA-330-3p functions as an oncogene in human esophageal cancer by targeting programmed cell death 4[J].Am J Cancer Res,2015,5(3):1062-1075.
[36]He X,Zhang Z,Li M,et al.Expression and role of oncogenic miRNA-224 in esophageal squamous cell carcinoma[J].BMC Cancer,2015,15:575.
[37]Hong L,Han Y,Zhang H,et al.The prognostic and chemotherapeutic value of miR-296 in esophageal squamous cell carcinoma[J].Ann Surg,2010,251(6):1056-1063.
[38]Zhang H,Li M,Han Y,et al.Down-regulation of miR-27a might reverse multidrug resistance of esophageal squamous cell carcinoma[J].Dig Dis Sci,2010,55(9):2545-2551.
[39]Imanaka Y,Tsuchiya S,Sato F,et al.MicroRNA-141 confers resistance to cisplatin-induced apoptosis by targeting YAP1 in human esophageal squamous cell carcinoma[J].J Hum Genet,2011,56(4):270-276.
[40]Hamano R,Miyata H,Yamasaki M,et al.Overexpression of miR-200c induces chemoresistanceinesophagealcancersmediated through activation of the Akt signaling pathway[J].Clin Cancer Res,2011,17(9):3029-3038.
[41]Ma J,Hong L,Xu G,et al.miR-483-3p plays an oncogenic role in esophageal squamous cell carcinoma by targeting tumor suppressor EI24[J].Cell Biol Int,2016,40(4):448-455.
[42]Kano M,Seki N,Kikkawa N,et al.miR-145,miR-133a and miR-133b:Tumor-suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma[J].Int J Cancer,2010,127(12):2804-2814.
[43]Wang F,Xia J,Wang N,et al.miR-145 inhibits proliferation and invasion of esophageal squamous cell carcinoma in part by targeting c-Myc[J].Onkologie,2013,36(12):754-758.
[44]Han Q,Zhang HY,Zhong BL,et al.MicroRNA-145 Inhibits Cell Migration and Invasion and Regulates Epithelial-Mesenchymal Transition(EMT)by Targeting Connective Tissue Growth Factor(CTGF)in Esophageal Squamous Cell Carcinoma[J].Med Sci Monit,2016,22:3925-3934.
[45]Cui XB,Li S,Li TT,et al.Targeting oncogenic PLCE1 by miR-145 impairs tumor proliferation and metastasis of esophageal squamous cell carcinoma[J].Oncotarget,2016,7(2):1777-1795.
[46]Akanuma N,Hoshino I,Akutsu Y,et al.MicroRNA-133a regulates themRNAsoftwoinvadopodia-relatedproteins,F(xiàn)SCN1and MMP14,in esophageal cancer[J].Br J Cancer,2014,110(1): 189-198.
[47]Li S,Qin X,Li Y,et al.MiR-133a suppresses the migration and invasion of esophageal cancer cells by targeting the EMT regulator SOX4[J].Am J Transl Res,2015,7(8):1390-1403.
[48]Yuan Y,Zeng ZY,Liu XH,et al.MicroRNA-203 inhibits cell proliferation by repressing ΔNp63 expression in human esophageal squamous cell carcinoma[J].BMC Cancer,2011,11:57.
[49]Takeshita N,Mori M,Kano M,et al.miR-203 inhibits the migration and invasion of esophageal squamous cell carcinoma by regulating LASP1[J].Int J Oncol,2012,41(5):1653-1661.
[50]Yu X,Jiang X,Li H,et al.miR-203 inhibits the proliferation and self-renewal of esophageal cancer stem-like cells by suppressing stem renewal factor Bmi-1[J].Stem Cells Dev,2014,23(6):576-585.
[51]Liu Q,Lv GD,Qin X,et al.Role of microRNA let-7 and effect to HMGA2 in esophageal squamous cell carcinoma[J].Mol Biol Rep,2012,39(2):1239-1246.
[52]Ding DP,Chen ZL,Zhao XH,et al.miR-29c induces cell cycle arrest in esophageal squamous cell carcinoma by modulating cyclin E expression[J].Carcinogenesis,2011,32(7):1025-1032.
[53]Matsushima K,Isomoto H,Yamaguchi N,et al.MiRNA-205 modulates cellular invasion and migration via regulating zinc finger E-box binding homeobox 2 expression in esophageal squamous cell carcinoma cells[J].J Transl Med,2011,9:30.
[54]Zhang M,Zhou S,Zhang L,et al.miR-518b is down-regulated,and involved in cell proliferation and invasion by targeting Rap1b in esophageal squamous cell carcinoma[J].FEBS Lett,2012,586(19):3508-3521.
[55]Zhang M,Yang Q,Zhang L,et al.miR-302b is a potential molecular marker of esophageal squamous cell carcinoma and functions as a tumor suppressor by targeting ErbB4[J].J Exp Clin Cancer Res,2014,33(1):10.
[56]Zhang M,Zhang P,Zhang L,et al.miR-302b regulates cancer related inflammation by targeting CXCR4 and IRF2 in esophageal squamous cell carcinoma[J].J Gastroenterol Hepatol,2015,30(Suppl 4):89-90.
[57]張鵬江,崔曼莉,張 超,等.炎癥相關細胞因子對食管癌細胞株miR-302b表達的影響[J].現(xiàn)代腫瘤醫(yī)學,2016,24(5):690-693.
[58]葉文廣,姚青林,張明鑫,等.miR-520a調(diào)控ErbB4的表達并抑制食管鱗癌細胞的增殖與侵襲[J].南方醫(yī)科大學學報,2014,34(2):164-168.
[59]張 超,張 蓉,樊晴伶,等.miR-520a在食管鱗癌組織中的表達及意義[J].現(xiàn)代腫瘤醫(yī)學,2015,23(20):2923-2925.
[60]Zhou S,Ye W,Ren J,et al.MicroRNA-381 increases radiosensitivity in esophageal squamous cell carcinoma[J].Am J Cancer Res,2015,5(1):267-277.
[61]Kong KL,Kwong DL,Chan TH,et al.MicroRNA-375 inhibits tumour growth and metastasis in oesophageal squamous cell carcinoma through repressing insulin-like growth factor 1 receptor[J].Gut,2012,61(1):33-42.
[62]Isozaki Y,Hoshino I,Nohata N,et al.Identification of novel molecular targets regulated by tumor suppressive miR-375 induced by histone acetylation in esophageal squamous cell carcinoma[J].Int J Oncol,2012,41(3):985-994.
[63]Osako Y,Seki N,Kita Y,et al.Regulation of MMP13 by antitumor microRNA-375 markedly inhibits cancer cell migration and invasion in esophageal squamous cell carcinoma[J].Int J Oncol,2016,49(6):2255-2264.
[64]Wang XC,Zhang ZB,Wang YY,et al.Increased miRNA-22 expression sensitizes esophageal squamous cell carcinoma to irradiation[J].J Radiat Res,2013,54(3):401-408.
[65]Ni Y,Meng L,Wang L,et al.MicroRNA-143 functions as a tumor suppressor in human esophageal squamous cell carcinoma[J].Gene,2013,517(2):197-204.
[66]Mao Y,Liu J,Zhang D,et al.miR-143 inhibits tumor progression by targeting FAM83F in esophageal squamous cell carcinoma[J].Tumour Biol,2016,37(7):9009-9022.
[67]Liu J,Mao Y,Zhang D,et al.MiR-143 inhibits tumor cell proliferation and invasion by targeting STAT3 in esophageal squamous cell carcinoma[J].Cancer Lett,2016,373(1):97-108.
[68]Fu MG,Li S,Yu TT,et al.Differential expression of miR-195 in esophageal squamous cell carcinoma and miR-195 expression inhibits tumor cell proliferation and invasion by targeting of Cdc42[J].FEBS Lett,2013,587(21):3471-3479.
[69]Zhang HF,Zhang K,Liao LD,et al.miR-200b suppresses invasiveness and modulates the cytoskeletal and adhesive machinery in esophageal squamous cell carcinoma cells via targeting Kindlin-2[J].Carcinogenesis,2014,35(2):292-301.
[70]Zhang HF,Alshareef A,Wu C,et al.Loss of miR-200b promotes invasion via activating the Kindlin-2/integrin β1/AKT pathway in esophageal squamous cell carcinoma:An E-cadherin-independent mechanism[J].Oncotarget,2015,6(30):28949-28960.
[71]He Z,Yi J,Liu X,et al.MiR-143-3p functions as a tumor suppressor by regulating cell proliferation,invasion and epithelial-mesenchymal transition by targeting QKI-5 in esophageal squamous cell carcinoma[J].Mol Cancer,2016,15(1):51.
[72]Zhang HF,Alshareef A,Wu C,et al.miR-200b induces cell cycle arrest and represses cell growth in esophageal squamous cell carcinoma[J].Carcinogenesis,2016,37(9):858-869.
[73]Zhu L,Wang Z,F(xiàn)an Q,et al.microRNA-27a functions as a tumor suppressor in esophageal squamous cell carcinoma by targeting KRAS[J].Oncol Rep,2014,31(1):280-286.
[74]Jiang Y,Duan Y,Zhou H.MicroRNA-27a directly targets KRAS to inhibit cell proliferation in esophageal squamous cell carcinoma[J].Oncol Lett,2015,9(1):471-477.
[75]Liu R,Yang M,Meng Y,et al.Tumor-suppressive function of miR-139-5p in esophageal squamous cell carcinoma[J].PLoS One,2013,8(10):e77068.
[76]Yuan X,He J,Sun F,et al.Effects and interactions of MiR-577 and TSGA10 in regulating esophageal squamous cell carcinoma[J].Int J Clin Exp Pathol,2013,6(12):2651-2667.
[77]Wang Y,Zang W,Du Y,et al.Mir-655 up-regulation suppresses cell invasion by targeting pituitary tumor-transforming gene-1 in esophageal squamous cell carcinoma[J].J Transl Med,2013,11:301.
[78]Li H,Meng F,Ma J,et al.Insulin receptor substrate-1 and Golgi phosphoprotein 3 are downstream targets of miR-126 in esophageal squamous cell carcinoma[J].Oncol Rep,2014,32(3):1225-1233.
[79]Nie ZC,Weng WH,Shang YS,et al.MicroRNA-126 is down-regulated in human esophageal squamous cell carcinoma and inhibits the proliferation and migration in EC109 cell via PI3K/AKT signaling pathway[J].Int J Clin Exp Pathol,2015,8(5):4745-4754.
[80]Liu R,Gu J,Jiang P,et al.DNMT1-microRNA126 epigenetic circuit contributes to esophageal squamous cell carcinoma growth via ADAM9-EGFR-AKT signaling[J].Clin Cancer Res,2015,21(4): 854-863.
[81]Zhang N,F(xiàn)u H,Song L,et al.MicroRNA-100 promotes migration and invasion through mammalian target of rapamycin in esophageal squamous cell carcinoma[J].Oncol Rep,2014,32(4):1409-1418.
[82]Tian H,Hou L,Xiong YM,et al.miR-218 suppresses tumor growth and enhances the chemosensitivity of esophageal squamous cell carcinoma to cisplatin[J].Oncol Rep,2015,33(2):981-989.
[83]Wang T,Chen T,Niu H,et al.MicroRNA-218 inhibits the proliferation and metastasis of esophageal squamous cell carcinoma cells by targeting BMI1[J].Int J Mol Med,2015,36(1):93-102.
[84]Qi Y,Li X,Zhao S.miR-29b inhibits the progression of esophageal squamous cell carcinoma by targeting MMP-2[J].Neoplasma,2015,62(3):384-390.
[85]Yan S,Jiang H,F(xiàn)ang S,et al.MicroRNA-340 Inhibits Esophageal Cancer Cell Growth and Invasion by Targeting Phosphoserine Aminotransferase 1[J].Cell Physiol Biochem,2015,37(1):375-386.
[86]He W,F(xiàn)eng J,Zhang Y,et al.microRNA-186 inhibits cell proliferation and induces apoptosis in human esophageal squamous cell carcinoma by targeting SKP2[J].Lab Invest,2016,96(3):317-324.
[87]Meng X,Chen X,Lu P,et al.MicroRNA-202 inhibits tumor progression by targeting LAMA1 in esophageal squamous cell carcinoma[J].Biochem Biophys Res Commun,2016,473(4):821-827.
[88]Jiang S,Zhao C,Yang X,et al.miR-1 suppresses the growth of esophageal squamous cell carcinoma in vivo and in vitro through the downregulation of MET,cyclin D1 and CDK4 expression[J].Int J Mol Med,2016,38(1):113-122.
[89]Mao Y,Li L,Liu J,et al.MiR-495 inhibits esophageal squamous cell carcinoma progression by targeting Akt1[J].Oncotarget,2016,7(32):51223-51236.
[90]Jin L,Yi J,Gao Y,et al.MiR-630 inhibits invasion and metastasis in esophageal squamous cell carcinoma[J].Acta Biochim Biophys Sin(Shanghai),2016,48(9):810-819.
[91]Li D,Shi M,Ji H,et al.MicroRNA-181d is a tumor suppressor in human esophageal squamous cell carcinoma inversely regulating Derlin-1[J].Oncol Rep,2016,36(4):2041-2048.
[92]Song C,Lu P,Shi W,et al.MiR-622 functions as a tumor suppressor and directly targets E2F1 in human esophageal squamous cell carcinoma[J].Biomed Pharmacother,2016,83:843-849.
[93]Gao X,Wang X,Cai K,et al.MicroRNA-127 is a tumor suppressor in human esophageal squamous cell carcinoma through the regulation of oncogene FMNL3[J].Eur J Pharmacol,2016,791:603-610.
[94]Jin YY,Chen QJ,Wei Y,et al.Upregulation of microRNA-98 increases radiosensitivity in esophageal squamous cell carcinoma[J].J Radiat Res,2016,57(5):468-476.
[95]Hou G,Yang S,Zhou Y,et al.Targeted inhibition of mTOR signaling improves sensitivity of esophageal squamous cell carcinoma cells to cisplatin[J].J Immunol Res,2014,2014:845763.
[96]Mallick R,Patnaik SK,Wani S,et al.A Systematic Review of Esophageal MicroRNA Markers for Diagnosis and Monitoring of Barrett's Esophagus[J].Dig Dis Sci,2016,61(4):1039-1050.
[97]Bobryshev YV,Orekhov AN,Chistiakov DA.MicroRNAs in Esophageal Adenocarcinoma:Functional Significance and Potential for the Development of New Molecular Disease Markers[J].Curr Pharm Des,2015,21(23):3402-3416.
[98]Van ZN,Pavlakis N,Kao S,et al.MesomiR 1:a phase I study of TargomiRs in patients with refractory malignant pleural mesothelioma(MPM)and lung cancer(NSCLC)[J].Ann Oncol,2015,26(suppl 2):ii16-ii19.
[99]Shah MY,F(xiàn)errajoli A,Sood AK,et al.microRNA Therapeutics in Cancer-An Emerging Concept[J].EBioMedicine,2016,12:34-42.
Function,mechanism and therapeutic prospect of miRNAs in esophageal squamous cell carcinoma
CUI Man-Li1,ZHOU Su-Na2,ZHANG Ming-Xin1,WANG Jing-Jie1
1Department of Gastroenterology,2Department of Radiotherapy,Tangdu Hospital,F(xiàn)ourth Military Medical University,Xi'an 710038,China
Esophageal squamous cell carcinoma(ESCC)dominates in East Asia,and almost one-half of ESCC cases in the world occur in China.Despite improvements in both diagnostic and therapeutic techniques,ESCC continues to show a poor prognosis.Therefore,the molecular mechanisms responsible for the deregulation in ESCC needs further research and investigation.MicroRNAs(miRNAs)represent a class of small,non-coding RNAs that regulate gene expression at the post-transcriptional levels.Studies showed that the dysregulation of miRNAs presents up-or down-regulation and deletion in different oncogenic pathways and/or various types of cancers,indicating that some miRNAs may serve as oncogenic or tumor suppressor genes.In this review,we summarize the related research progress on expression,function,mechanism and therapeutic prospect of miRNAs in ESCC.
function;mechanism;therapeuticprospect;miRNAs;esophageal squamous cell carcinoma
R735.1
A
2095-6894(2017)01-11-09
2016-11-21;接受日期:2016-12-10
國家自然基金(81302055,81301922),唐都醫(yī)院精英才人計劃后備人才項目
崔曼莉.碩士,主治醫(yī)師.研究方向:消化道腫瘤.E-mail: cuiml1587@163.com
張明鑫.博士,副主任醫(yī)師.研究方向:消化道腫瘤臨床及基礎研究.E-mail:zmx3115@163.com