李飄飄,包珊
(1.南華大學(xué),湖南衡陽421001;
2.海南省人民醫(yī)院婦科,海南海口570100)
·綜述·
子宮內(nèi)膜癌中miRNA與自噬的研究進(jìn)展
李飄飄1,2,包珊2
(1.南華大學(xué),湖南衡陽421001;
2.海南省人民醫(yī)院婦科,海南海口570100)
miRNAs涉及多種生理和病理過程,近期研究其與腫瘤的關(guān)系密切,自噬作為細(xì)胞在異常環(huán)境中維持生存的一種方式近年也備受關(guān)注。miR和自噬涉及真核細(xì)胞基因表達(dá)、發(fā)育分化、凋亡、應(yīng)激等多方面調(diào)控,廣泛參與免疫防御、腫瘤抑制等多種生理和病理過程,二者與腫瘤的相關(guān)研究成為學(xué)者爭相探究的熱點(diǎn)。miR可對(duì)自噬多個(gè)環(huán)節(jié)產(chǎn)生調(diào)控作用,其調(diào)控自噬對(duì)腫瘤的促/抑作用為腫瘤的治療提供新的靶點(diǎn)。該文就miR、自噬在子宮內(nèi)膜癌的表達(dá)以及miR調(diào)控自噬對(duì)子宮內(nèi)膜癌等惡性腫瘤發(fā)生發(fā)展作用的相關(guān)研究進(jìn)行綜述。
子宮內(nèi)膜癌;自噬;miR
子宮內(nèi)膜癌(Endometrial carcimoma,EEC)為發(fā)生于子宮內(nèi)膜的一組上皮性惡性腫瘤,是當(dāng)今女性生殖系統(tǒng)三大惡性腫瘤之一,高發(fā)年齡在58~61歲,發(fā)病率約占女性生殖器惡性腫瘤的50%,居女性全身惡性腫瘤第4位,病死率居女性全身惡性腫瘤第8位[1]。近年來發(fā)病率略有上升趨勢,在我國僅次于子宮頸癌,居女性生殖系統(tǒng)惡性腫瘤的第二位[2]。其致癌機(jī)制尚不清楚,探索致癌機(jī)制、攻克這一疾病是目前亟待解決的問題,本文將圍繞對(duì)miR、自噬與子宮內(nèi)膜癌的相關(guān)研究進(jìn)行綜述。
微小RNA(Micro RNA,miR)是一類新發(fā)現(xiàn)的可調(diào)控基因表達(dá)的內(nèi)源性非編碼單鏈小分子RNA,長19~22 nt,通過與靶mRNA特異的堿基配對(duì)(miR與靶mRNA3'非翻譯區(qū)域即3'UTR結(jié)合)引起靶mRNA降解或者翻譯抑制,在轉(zhuǎn)錄后水平對(duì)基因進(jìn)行調(diào)控[3]。研究表明,miR在人類多種疾病的發(fā)生、發(fā)展中有不同程度的參與和表達(dá),尤其是腫瘤疾病方面。不同的miR對(duì)細(xì)胞生長具有不同的調(diào)控作用,相同的miR對(duì)不同細(xì)胞株的調(diào)控作用亦不同,而且miR可調(diào)節(jié)眾多癌基因和抑癌基因,在腫瘤中miR表達(dá)異常上調(diào)或下調(diào)。高表達(dá)的miR常出現(xiàn)在腫瘤細(xì)胞基因擴(kuò)增區(qū)域,而低表達(dá)的miR常出現(xiàn)在基因缺失區(qū)域,前者導(dǎo)致腫瘤抑制物水平的下調(diào),而后者導(dǎo)致抑癌基因的上調(diào)。Wu等[4]利用基因芯片檢測10組子宮內(nèi)膜組織,與對(duì)照組相比,子宮內(nèi)膜癌組織中17 miRs表達(dá)上調(diào),其中miR-200b、miR-200c、miR-429(miR-200家族)過度表達(dá),其與順鉑治療的耐藥性有關(guān),6個(gè)miRs表達(dá)下調(diào)。提示上述miR可作為腫瘤標(biāo)志物為子宮內(nèi)膜癌的早期診治提供新的手段。研究發(fā)現(xiàn),性激素的分泌能影響子宮內(nèi)膜中miR表達(dá)水平,而microRNA的異常表達(dá)可以造成子宮內(nèi)膜癌的發(fā)生、發(fā)展[5]。Boren等[6]發(fā)現(xiàn)13個(gè)miR和90個(gè)mRNA與子宮內(nèi)膜癌的發(fā)生有關(guān),其中在子宮內(nèi)膜癌中表達(dá)升高的miR包括miR-185、miR-106a、miR-181a、miR-210、miR-423、miR-103、miR-107等。Torres等[7]研究結(jié)果顯示子宮內(nèi)膜癌組織中的miR-21的濃度比正常子宮內(nèi)膜組織高2.312倍。Karaayvaz等[8]對(duì)48對(duì)正常子宮內(nèi)膜組織和子宮內(nèi)膜癌組織中的miR-200C和miR-205表達(dá)水平進(jìn)行實(shí)時(shí)定量PCR測定,對(duì)其靶蛋白PTEN的表達(dá)量進(jìn)行免疫組化測定,發(fā)現(xiàn)miR-200C和miR-205在子宮內(nèi)膜癌組織中均過度表達(dá),PTEN的表達(dá)量與miR-205的水平呈負(fù)相關(guān),證明miR-205的表達(dá)水平與患者的存活率顯著相關(guān)。上述均可提示miR這一腫瘤調(diào)控分子在子宮內(nèi)膜癌發(fā)生、發(fā)展、預(yù)后轉(zhuǎn)歸中均有不同程度的參與和表達(dá)。
自噬是1962年由Ashford和Porten首先提出的一種細(xì)胞自我吞噬現(xiàn)象[9]。自噬現(xiàn)象是真核細(xì)胞普遍存在的,在正常細(xì)胞和腫瘤細(xì)胞中均存在,在正常細(xì)胞中自噬可清除胞內(nèi)受損的細(xì)胞器和細(xì)胞代謝產(chǎn)生的廢物,避免細(xì)胞代謝產(chǎn)生的廢物積聚而引起各種突變的發(fā)生,因此有效的減少了腫瘤的發(fā)生。在腫瘤細(xì)胞中,腫瘤細(xì)胞生長旺盛,迅速向周圍組織浸潤蔓延,當(dāng)其細(xì)胞所需的營養(yǎng)不足時(shí),腫瘤細(xì)胞自噬被啟動(dòng),可通過降解胞內(nèi)大分子蛋白質(zhì)及受損細(xì)胞器以提供營養(yǎng),腫瘤細(xì)胞獲得營養(yǎng)后細(xì)胞壽命延長,此時(shí),自噬可以緩解腫瘤細(xì)胞的代謝壓力,發(fā)揮的是促進(jìn)腫瘤細(xì)胞生存的作用[10]。研究發(fā)現(xiàn),某些腫瘤如乳腺癌[11]、肝癌[12]、卵巢癌[13]等腫瘤細(xì)胞自噬水平低于正常細(xì)胞。因此,自噬在腫瘤發(fā)展的不同階段,有不同的作用機(jī)制,大多學(xué)者認(rèn)為自噬活性的增高可以抑制腫瘤的發(fā)生、發(fā)展。自噬對(duì)腫瘤的抑制作用不僅僅是自噬性細(xì)胞死亡,而是由一系列基因嚴(yán)格調(diào)控多種機(jī)制共同作用的生物學(xué)過程,多種癌基因和抑癌基因通過參與自噬途徑而發(fā)揮抗腫瘤效應(yīng),如Beclin1、PTEN、DAPK、PI3K、Bcl-2等,因此,自噬調(diào)控的異常與腫瘤的發(fā)生有著直接的關(guān)系[14]。
目前雖無子宮內(nèi)膜癌自噬的直接報(bào)道,但已經(jīng)開展了在EEC中自噬相關(guān)基因表達(dá)的報(bào)道,如ARHI、Beclin1和PTEN。Qu等[15]發(fā)現(xiàn),ARHI蛋白在子宮內(nèi)膜腺癌組織中表達(dá)下調(diào),提示其表達(dá)降低與子宮內(nèi)膜腺癌的發(fā)生有關(guān),可能成為診斷早期子宮內(nèi)膜腺癌的指標(biāo)之一。且ARHI蛋白表達(dá)與腫瘤細(xì)胞分化程度,手術(shù)病理分期,肌層浸潤深度及淋巴結(jié)轉(zhuǎn)移相關(guān),提示ARHI蛋白表達(dá)可以作為子宮內(nèi)膜腺癌評(píng)估預(yù)后的因素。Zhao等[16]發(fā)現(xiàn)Beclin1在正常子宮內(nèi)膜組織、子宮內(nèi)膜增殖癥、子宮內(nèi)膜癌組織中的表達(dá)率逐漸下降,Qu等[15]發(fā)現(xiàn)Beclin1蛋白在正常子宮內(nèi)膜到子宮內(nèi)膜腺癌表達(dá)逐漸下調(diào),說明Beclin1在子宮內(nèi)膜腺癌的發(fā)生過程中可能起著一定的作用。Qian等[17]研究表明PTEN與子宮內(nèi)膜癌臨床病理參數(shù)關(guān)系的分析表明,PTEN蛋白表達(dá)與腫瘤病理類型、細(xì)胞分化程度、肌層浸潤深度相關(guān),而這三者是子宮內(nèi)膜癌最重要的預(yù)后相關(guān)因素,由此可見,PTEN蛋白表達(dá)與否還能預(yù)示子宮內(nèi)膜癌患者的預(yù)后。王煥等[18]研究發(fā)現(xiàn):RAD001可以誘導(dǎo)腫瘤細(xì)胞自噬和增強(qiáng)細(xì)胞對(duì)放療的敏感性,從而抑制人子宮內(nèi)膜癌Ishikawa細(xì)胞及HEC-1A細(xì)胞的增殖;誘導(dǎo)Ishikawa細(xì)胞和HEC-1A細(xì)胞發(fā)生自噬性細(xì)胞死亡。
在腫瘤形成的初始階段,自噬缺陷會(huì)導(dǎo)致細(xì)胞癌變促腫瘤形成,這時(shí)自噬起抑癌作用。惡性增殖的腫瘤細(xì)胞需要應(yīng)對(duì)營養(yǎng)缺乏、低氧等不良微環(huán)境,自噬通過循環(huán)利用細(xì)胞內(nèi)營養(yǎng)物質(zhì),為腫瘤的生存提供營養(yǎng)和能量,發(fā)揮促癌功能;上述研究顯示miR在自噬多個(gè)關(guān)鍵環(huán)節(jié)均能調(diào)控自噬,人們開始探究miR調(diào)控自噬對(duì)腫瘤的生長、發(fā)展、轉(zhuǎn)歸的影響,已有不少學(xué)者對(duì)不同腫瘤細(xì)胞中miR調(diào)控自噬所起的抑/促癌作用進(jìn)行探究,也有研究發(fā)現(xiàn)在子宮內(nèi)膜癌細(xì)胞中同樣存在可以調(diào)控自噬的miR,而此類miR通過調(diào)控自噬可以對(duì)子宮內(nèi)膜癌的發(fā)展、治療、預(yù)后轉(zhuǎn)歸起什么樣積極或者消極的影響,尚無學(xué)者涉及,這也是后續(xù)研究可以深入探究的方向。以下將概述miR在各腫瘤細(xì)胞中調(diào)控自噬起抑/促癌效應(yīng)。
3.1 miR調(diào)控自噬抑癌研究發(fā)現(xiàn):miR-375在肝癌細(xì)胞中濃度很低,當(dāng)肝癌細(xì)胞在缺氧環(huán)境中誘發(fā)自噬時(shí),穩(wěn)定轉(zhuǎn)染miR-375能明顯抑制自噬流,從而使腫瘤生長受限[19];在抑癌基因VHL丟失的腎癌細(xì)胞內(nèi)miR-204水平極低,通過增加細(xì)胞內(nèi)miR-204含量能使饑餓狀態(tài)下的細(xì)胞不能產(chǎn)生完整的自噬體,導(dǎo)致腫瘤增殖受限[20];miR-376和miR-101明顯抑制乳癌細(xì)胞的自噬流[21-23]。由上述結(jié)果可知有些miRNA在腫瘤細(xì)胞中的表達(dá)明顯低于正常細(xì)胞,通過人為增加這些miRNA在腫瘤細(xì)胞中的含量能有效抑制自噬流,導(dǎo)致腫瘤細(xì)胞不能耐受代謝應(yīng)激而死亡。對(duì)自噬起直接負(fù)性調(diào)控的“門衛(wèi)”mTOR是has-miR-100、has-miR-99a、has-miR-199a-3p的強(qiáng)作用靶[24],而has-miR-100、has-miR-99a、has-miR-199a-3p在子宮內(nèi)膜癌中表達(dá)下調(diào)[25]。所以通過轉(zhuǎn)染這些miRNA在子宮內(nèi)膜癌中的含量,也可能有效抑制自噬流,導(dǎo)致腫瘤細(xì)胞不能耐受代謝應(yīng)激而死亡。mTOR是自噬通路中起門控作用的負(fù)性調(diào)控蛋白,也是has-miR-100、has-miR-99a、has-miR-199a-3p的強(qiáng)作用靶,在子宮內(nèi)膜癌細(xì)胞中轉(zhuǎn)染這些低表達(dá)的miR、沉默mTOR,有可能提高子宮內(nèi)膜癌細(xì)胞自噬來誘導(dǎo)子宮內(nèi)膜癌細(xì)胞自噬性死亡,這將為子宮內(nèi)膜癌的診治提供新的靶點(diǎn)。
3.2 miR調(diào)控自噬促癌研究發(fā)現(xiàn)胰腺細(xì)胞經(jīng)致癌物質(zhì)誘導(dǎo)后在癌變前期自噬能力增強(qiáng),這時(shí)若抑制自噬將導(dǎo)致癌前細(xì)胞的持續(xù)增殖,而當(dāng)癌變完成后腫瘤細(xì)胞的自噬能力反而降低[26]。也有研究指出:在甲狀腺髓樣癌細(xì)胞中miR-183過度表達(dá),它通過抑制LC3B對(duì)自噬起負(fù)調(diào)控作用,但促癌miR-183是防止了細(xì)胞自噬死亡還是在成瘤階段抑制維持機(jī)體穩(wěn)態(tài)的自噬尚不清楚[27]。促癌基因miR-31能直接靶向缺氧誘導(dǎo)因子抑制劑HIF-1,使缺氧誘導(dǎo)因子HIFα表達(dá)上調(diào),間接誘導(dǎo)自噬產(chǎn)生,使腫瘤細(xì)胞高速增殖[28]。
miR的發(fā)現(xiàn)是RNA研究領(lǐng)域的重要突破,為人們提供了一種全新的視角來認(rèn)識(shí)生物基因和基因表達(dá)調(diào)節(jié)的本質(zhì),其有促/抑癌基因的作用,自噬在腫瘤生長生長、發(fā)展也有雙刃劍作用。眾多miRNA通過對(duì)自噬水平的調(diào)控對(duì)腫瘤的結(jié)局起關(guān)鍵作用,miR是否可以通過mTOR調(diào)控子宮內(nèi)膜癌細(xì)胞自噬尚未有學(xué)者涉入。現(xiàn)有研究均提示子宮內(nèi)膜癌較正常增生內(nèi)膜自噬活性明顯降低,mTOR是多個(gè)miR的強(qiáng)作用靶,mTOR亦是調(diào)控自噬的門衛(wèi),深入探討miR、自噬和子宮內(nèi)膜癌之間相互關(guān)系及是否存在互通的調(diào)控機(jī)制,將為子宮內(nèi)膜癌的診治提供新的靶點(diǎn)。
[1]Jemal A,Siegel R,Xu JQ,et al.Cancer statistic 2010[J].CA Cancer J Clin,2010,60(5):277-300.
[2]Yi XF,Zheng WX.Classification of endometrial carcinoma and clinical significance[J].Chinese Journal of Practical Gynecology and Obstetrics,2008,24(1):15-19.
[3]Bartel DP.MicroRNAs:targetrecognitionandregulatory functions [J].Cell,2009,136(2):215-233.
[4]Wu W,Lin Z,Zhuang Z,et al.Expression profile of mammalian micro RNAs in endometrioid adenocarcinoma[J].Eur J Cancer Prev, 2009,18(1):50-55.
[5]Kanzawa T,Kondo Y,Ito H,et al.Induction of autophagic cell death in malignant glioma cells by arsenic trioxide[J].Cancer Res, 2003,63(9):2103-2108.
[6]Boren T,Xiong Y,Hakam A.MicroRNAs and their targetmessenger RNAs associated with endometrial carcinogenesis[J].Gynecol Oncol,2008,110:206-215.
[7]TorresA,Torres K,PaszkowskiT,et al.Highly increased maspin expression corresponds with up-regulation of mir-21 in endometrial cancer a preliminaryreport[J].Int JGynecolCancer,2011,21(1):8-14.
[8]Karaayvaz M,Zhang C,Liang S,et al.Prognostic Significance of miR-205 in endometrial Cancer[J].P Los One,2012,7(4):e35158.
[9]Ashford TP,Porter KR.Cytoplasmic componengts in hepatic cell lysosomes[J].J Cell Biol,1962,12(1):198-202.
[10]Kabeya Y,Mizushima N,Ueno T,et al.LC3,a mammalian homologue of yeast Apg8p,is localized in autophagosome membranes after processing[J].EMBO,2000,19:5720-5728.
[11]Ding ZB,Shi YH,Zhou J,et al.Association of autophagy defect with a malignant phenotype and poor prognosis of hepatocellular carcinoma[J].Cancer Res,2008,68(22):9167-9175.
[12]Feng W,Marquez RT,Lu Z.et al.Imprinted tumor suppressor genes ARHI and PEG3 are the most frequently down-regulated in human ovarian cancers by loss of heterozygosity and promoter methylation[J].Cancer,2008,l12(7):1489-1502.
[13]Wang L,Hoque A,Luo RZ,et a1.Loss of the expression of the tumor suppressor gene ARHI is associated with progression of breast cancer[J].Clin Cancer Res,2003,9(10pt 1):3660-3666.
[14]Scott RC,Juhasz G,Neufeld TP.Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic cell death[J].Curr Biol,2007,17(1):1-11.
[15]Qu CP、Wang QY.The Expression and the Clinical Significance of Autophagy-relatedGene ARHI and Beclin1 in endometrial adenocarcinoma tissues[D].Jilin University,2013.
[16]Zhao JH,Wan XY,Xie X,et al.Expression and clinical significance of Becline and PTEN in endometrial carcinoma[J].Ai Zheng, 2006,25(6):753-757.
[17]Qian XQ,Wang XY.Prinary research in the change of the autophage activity in carciiogenesis and development of endometrioid adenocarcinoma,2008,17(7):517-519.
[18]Wang H,Li XM,Liu S,et al.RAD001 promotes chemotherapeutic sensitivity of human endometrialcarcinoma cells to paclitaxel via inducing autophagy[J].Chinese Journal of Pathophysiology,2013,29 (11):1966-1971.
[19]Chang Y,Yan W,He X,et al.miR-375 inhibits autophagy and reduces viability of hepatocellular carcinoma cells under hypoxic conditions[J].Gastroenterology,2012,143(1):177-187.
[20]Xiao J,Zhu X,He B,et al.MiR-204 regulates cardiomyocyte autophagy induced by ischemia-reperfusion through LC3-Ⅱ[J].J Biomed Sci,2011,18:35.
[21]Korkrnaz G,1e Sage C,Tekirdag KA,et al.miR-376b controls starvation and mTOR inhibition-related autophagy by targeting ATG4C and BECN1[J].Autophagy,2012,8(2):165-176.
[22]Huang Y,Guerrero-preston R,Ratovitski EA.Phospho-Delta NP63 alpha-dependent regulation of autophagic signaling through transcription and micro-RNA modulation[J].Cell Cycle,2012,11(6): 1247-1259.
[23]Frankel LB,Wen J,Lees M,et al.microRNA-101 is a potent inhibitor of autophagy[J].EMBO J,2011,30(22):4628-4641.
[24]Dong Wu,Hui-juan Huang,Chun-ni He,et al.MicroRNA-199a-3p Regulates Endometrial Cancer Cell Proliferation by Targeting Mammalian Target of Rapamycin(mTOR)[J].International Journal of Gynecological Cancer,2003,23(7),2013.
[25]Anna Torres,Kamil Torres,Anna Pesci,et al.Deregulation of miR-100,miR-99a and miR-199b in tissues and plasma coexists with increased expression of mTOR kinase in endometrioid endometrial carcinoma[J].BMC Cancer,2012,12:369.
[26]Toth S,Nagy K,palfia Z,et al.Changes in cellular autophagic capacify duringazaserine-initiatedpancreaticcarcinogenes[J].BiolHung,2001,52(4):393-401.
[27]Abraham D,Jackson N,Gundara JS,et al.MicroRNA profiling of sporadic and hereditary medullary thyroid cancer identifies predictors of nodal metastasis,prognosis,and potential therapeutic targets[J].Clin Cancer Res,2011,17(14):4772-4781.
[28]Pavlides S,Tsirigos A,Migneco G,et al.The autophagic tumor stroma model of cancer:Role of oxidative stress and ketone production in fueling tumor cell metabolism[J].Cell Cyc1e,2010,9(17): 3485-3505.
Research advances on miRNA and autophagy in endometrial carcinoma.
LI Piao-piao1,2,BAO Shan2.1. University of South China,Hengyang 421001,Hunan,CHINA;2.Department of Gynaecology,People's Hospital of Hainan Province,Haikou 570100,Hainan,CHINA
miRNAs is involved in many physiological and pathological processes,which has been showed to have close relationship with tumor.Autophagy,as a mode of existence for cells in the abnormal environment,has also attracted much attention in recent years.The concepts of miR and autophagy are related to gene expression in eukaryotic cells,development and differentiation,apoptosis,stress control,and are involved widely in immune defense,tumor suppression,as well as various physiological and pathological processes.The correlation between miR,autophagy and tumor has become the hot destination of scholars to explore.miR can regulate autophagy in multiple links.It can regulate the promoting or inhibiting effect of autophagy to tumors and provide a new target for treatment.This article will review the expression of miR,autophagy in endometrial carcinoma and functions that miR regulate autophagy in tumors.
Endometrial carcinoma;Autophagy;miR
R737.33
A
1003—6350(2014)21—3201—03
10.3969/j.issn.1003-6350.2014.21.1254
2014-07-04)
海南省自然科學(xué)基金(編號(hào):812148)
通迅作者:包珊。E-mial:baoshan3@126.com