李　龍　黃洪章

中山大學(xué)光華口腔醫(yī)學(xué)院?附屬口腔醫(yī)院口腔頜面外科廣東省口腔醫(yī)學(xué)重點(diǎn)實(shí)驗(yàn)室 廣州 510055

微小RNA-205在腫瘤化學(xué)治療耐藥中的作用和機(jī)制

李龍黃洪章

中山大學(xué)光華口腔醫(yī)學(xué)院?附屬口腔醫(yī)院口腔頜面外科廣東省口腔醫(yī)學(xué)重點(diǎn)實(shí)驗(yàn)室 廣州 510055

腫瘤對(duì)化學(xué)治療藥物的耐藥常導(dǎo)致化學(xué)治療失敗，腫瘤耐藥是臨床治療的一大難題。腫瘤的化學(xué)治療耐藥涉及多基因多信號(hào)轉(zhuǎn)導(dǎo)通路的復(fù)雜調(diào)控過程，其機(jī)制迄今不明。微小RNA（miRNA）是由一類長(zhǎng)18～25堿基組成的內(nèi)源性非編碼單鏈小RNA分子，在調(diào)節(jié)多種細(xì)胞生物學(xué)過程中起著重要的作用。miRNA的異常表達(dá)與腫瘤的發(fā)生進(jìn)展、遷移及化學(xué)治療耐藥存在密切的關(guān)系，而miRNA-205（miR-205）在腫瘤化學(xué)治療耐藥中起重要的調(diào)控作用，但其具體機(jī)制尚不清楚。本文就miR-205及其在腫瘤化學(xué)治療耐藥中的作用和機(jī)制等研究進(jìn)展作一綜述。

微小RNA-205； 腫瘤； 化學(xué)治療耐藥

化學(xué)治療是腫瘤治療的重要手段之一，但腫瘤細(xì)胞對(duì)化學(xué)藥物產(chǎn)生的耐藥現(xiàn)象極易導(dǎo)致治療失敗?；瘜W(xué)治療耐藥是多因素作用的結(jié)果，機(jī)制尚不清楚，其影響因素包括腫瘤組織內(nèi)血壓及血流量調(diào)節(jié)功能異常導(dǎo)致的化學(xué)治療藥物吸收不足而有效藥物質(zhì)量濃度降低[1-2]，細(xì)胞內(nèi)外環(huán)境改變導(dǎo)致細(xì)胞對(duì)藥物吸附能力降低[3-4]，從而降低細(xì)胞對(duì)藥物的吸收或增加藥物的排出與失活[5-6]，DNA損傷修復(fù)[7]，對(duì)程序性細(xì)胞死亡途徑的干擾進(jìn)而抑制程序性細(xì)胞死亡[8]，相關(guān)信號(hào)轉(zhuǎn)導(dǎo)通路激活介導(dǎo)化學(xué)治療耐藥等等。諸多研究[9-10]證實(shí)，微小RNA（microRNA，miRNA）的表達(dá)水平與腫瘤發(fā)生發(fā)展以及化學(xué)治療耐藥間存在著密切的聯(lián)系。miRNA的多態(tài)性常常導(dǎo)致miRNA對(duì)靶基因的調(diào)控作用削弱或增強(qiáng)，影響腫瘤細(xì)胞對(duì)藥物的吸收和代謝等功能。此外，miRNA異常表達(dá)可改變腫瘤細(xì)胞與藥物作用靶點(diǎn)的結(jié)合[11]并異常調(diào)控細(xì)胞增殖、程序性細(xì)胞死亡[12]等基本生物學(xué)過程，在腫瘤細(xì)胞對(duì)抗化學(xué)治療藥物方面起重要作用[13]。miRNA-250（miR-205）異常表達(dá)與多腫瘤的化學(xué)治療耐藥相關(guān)。如在膽管癌腫瘤細(xì)胞系中，miR-205過表達(dá)可提高膽管癌細(xì)胞對(duì)吉西他濱藥物的敏感性[14]，而在非小細(xì)胞肺癌細(xì)胞系中，miR-205過表達(dá)反而提高非小細(xì)胞肺癌細(xì)胞對(duì)順鉑的耐藥性[15]。Vera等[16]通過對(duì)多黑色素瘤細(xì)胞遺傳特征的檢測(cè)發(fā)現(xiàn)，miR-205異常表達(dá)也與化學(xué)治療耐藥性密切相關(guān)；因此以miR-205作為新的切入點(diǎn)，深入了解化學(xué)治療耐藥的分子機(jī)制可為腫瘤化學(xué)治療開辟新的途徑。

1　miR-205

miR-205是高度保守的小RNA分子，位于染色體1q32.2位置，其前體miR-205位于LOC642587基因的第二內(nèi)含子和第三外顯子連接處，常以與miR-200家族結(jié)合的表達(dá)形式發(fā)揮作用[17]，與不同的物種存在著同源性。人種屬來源的miR-205是基于小鼠和鲀科動(dòng)物其序列高度保守性利用計(jì)算機(jī)掃描技術(shù)預(yù)測(cè)[18]獲得的，后來在斑馬魚和人[19]種屬中進(jìn)一步確認(rèn)。miR-205在組織和細(xì)胞表達(dá)上具有一定特異性。miR-205主要在上皮表達(dá)，尤其是在鱗狀上皮表達(dá)具有高度特異性[20]。例如在斑馬魚中，miR-205的主要在上皮表達(dá)[21]；在小鼠中，表達(dá)于舌、角膜上皮和腳掌表皮等上皮部位[22]。miR-205參與了多種細(xì)胞生命活動(dòng)，其表達(dá)水平不同可以影響細(xì)胞的增殖和分化等生物學(xué)功能[23]。在上皮組織細(xì)胞形態(tài)發(fā)生[24]和上皮功能維持過程中起較重要作用[25]。此外，miR-205通過抑制低密度脂蛋白受體相關(guān)蛋白1或血管內(nèi)皮生長(zhǎng)因子-A的表達(dá)來抑制腫瘤細(xì)胞的侵襲，或通過結(jié)合特定抑癌基因抑制腫瘤細(xì)胞的增殖分化[26-28]。miR-205在不同的腫瘤中表達(dá)水平不一，miR-205在前列腺癌、乳腺癌和食管癌中的表達(dá)呈明顯下調(diào)，而在腎癌、膀胱癌和卵巢癌]細(xì)胞中表達(dá)上調(diào)[20,25,29-30]。

2　miR-205在腫瘤化學(xué)治療耐藥中的作用

miR-205在腫瘤化學(xué)治療的耐藥過程中起著重要作用，其相關(guān)作用機(jī)制尚不清楚。Puhr等[31]在構(gòu)建前列腺癌多西他賽耐藥細(xì)胞株過程中發(fā)現(xiàn)：腫瘤細(xì)胞在藥物篩選過程中出現(xiàn)上皮間質(zhì)轉(zhuǎn)化（epithelial-mesenchymal transition，EMT），在多西他賽處理的腫瘤細(xì)胞系或取自多西他賽藥物化學(xué)治療患者的組織標(biāo)本中，內(nèi)皮鈣黏著蛋白（endothelial-cadherin，E-cad）的表達(dá)水平明顯降低，同時(shí)miR-205的表達(dá)水平也相應(yīng)降低；在耐藥細(xì)胞系中，E-cad的表達(dá)缺失可導(dǎo)致miR-205和miR-200c表達(dá)下調(diào)，反過來上調(diào)miR-205和miR-200c也可導(dǎo)致E-cad的表達(dá)上調(diào)；因此，miR-205很可能參與調(diào)控EMT而在腫瘤細(xì)胞耐藥產(chǎn)生中發(fā)揮作用。Okamoto等[15]利用基因芯片技術(shù)對(duì)兩個(gè)膽管癌細(xì)胞系（HuH28和HuCCT1）進(jìn)行篩選發(fā)現(xiàn)，miR-205在相對(duì)耐藥的腫瘤細(xì)胞系中表達(dá)下調(diào)，上調(diào)miR-205表達(dá)水平后可明顯提高膽管癌細(xì)胞對(duì)吉西他濱的敏感性。

在前列腺癌腫瘤細(xì)胞中，miR-205通過介導(dǎo)抗B細(xì)胞淋巴瘤/白血病基因（B cell lymphoma/ leukmia，BCL）2L2程序性細(xì)胞死亡基因在前列腺癌腫瘤細(xì)胞耐藥中發(fā)揮作用；在前列腺癌中，miR-205表達(dá)下調(diào)可抑制化學(xué)治療誘導(dǎo)的程序性細(xì)胞死亡水平，進(jìn)一步提高腫瘤細(xì)胞對(duì)藥物的耐藥性；miR-205通過與靶基因BCL2L2的3'非編碼區(qū)（untranslated region，UTR）部分序列結(jié)合，下調(diào)BCL-w表達(dá)水平后miR-205表達(dá)上調(diào)，而miR-205過表達(dá)后卻又進(jìn)一步促進(jìn)腫瘤細(xì)胞對(duì)藥物的敏感性[32]。在非小細(xì)胞肺癌中，miR-205可負(fù)調(diào)控同源性第10號(hào)染色體缺失的磷酸酶和張力蛋白同源基因（phosphatase and tensin homology deleted on chromosome ten，PTEN），miR-205與PTEN的3' UTR位點(diǎn)結(jié)合，上調(diào)miR-205的表達(dá)水平后，可促進(jìn)非小細(xì)胞肺癌腫瘤細(xì)胞的生長(zhǎng)、遷移和侵襲，增強(qiáng)腫瘤細(xì)胞的耐藥性；而miR-205敲除后，可抑制以上細(xì)胞生命活動(dòng)，明顯提高PTEN的表達(dá)水平，而上調(diào)PTEN表達(dá)水平可抑制miR-205在腫瘤細(xì)胞中的表達(dá)[33]。

miR-205可靶向調(diào)控P73，與E2F1和DNp73等形成復(fù)雜調(diào)控網(wǎng)絡(luò)。體內(nèi)外研究[16,34]顯示：上調(diào)miR-205表達(dá)水平后可促進(jìn)腫瘤細(xì)胞的程序性死亡并抑制瘤體的生長(zhǎng)；敲除miR-205后，BCL2和相關(guān)轉(zhuǎn)運(yùn)蛋白表達(dá)水平也相應(yīng)上調(diào)，進(jìn)而促進(jìn)腫瘤細(xì)胞的耐藥作用。此外，miR-205還可通過調(diào)控細(xì)胞的自噬過程增強(qiáng)腫瘤細(xì)胞對(duì)化學(xué)治療藥物的解毒作用，進(jìn)而提高腫瘤細(xì)胞對(duì)化學(xué)治療藥物的耐藥性[35]。

3　miR-205在腫瘤化學(xué)治療中耐藥的機(jī)制

miR-205在腫瘤化學(xué)治療耐藥研究領(lǐng)域日趨成為熱點(diǎn)，但其在腫瘤中的生物學(xué)特性及作用尚不清楚。研究[36]顯示，無論是臨床組織標(biāo)本還是腫瘤細(xì)胞系，miR-205在鱗狀細(xì)胞癌中的表達(dá)水平均較其他腫瘤要高。在口腔鱗狀細(xì)胞癌中，miR-205在腫瘤鱗狀上皮的表達(dá)具有高度特異性，且與腫瘤的轉(zhuǎn)移與否有密切關(guān)系；miR-205的表達(dá)率在具有轉(zhuǎn)移性的惡性腫瘤組織標(biāo)本中較高，而在良性組織標(biāo)本中幾乎無表達(dá)，在健康組織上皮或基質(zhì)中并未見明顯表達(dá)[37]。研究[38-39]顯示，miR-205的激活與DNA低甲基化水平有關(guān)，與腫瘤遷移無明顯關(guān)系，與腫瘤干細(xì)胞形成密切相關(guān)。在健康組織癌變過程中，miR-205通過抑制EMT來維持上皮細(xì)胞的干性，從而促進(jìn)腫瘤細(xì)胞侵襲遷移[40]。

Kim等[41]通過檢測(cè)口腔癌上皮細(xì)胞生物學(xué)功能發(fā)現(xiàn)：miR-205在口腔癌上皮細(xì)胞系中具有抑癌作用，其表達(dá)水平低于其他口腔健康的角化細(xì)胞；此外，上調(diào)miR-205表達(dá)水平后，miR-205通過激活半胱氨酸天冬酰胺特異蛋白酶（cysteinyl aspartale specific protease，caspase）-3/7等程序性細(xì)胞死亡蛋白酶，促進(jìn)上皮程序性細(xì)胞死亡和提高口腔癌上皮細(xì)胞的細(xì)胞毒性；上調(diào)miR-205表達(dá)水平后，可以直接與白細(xì)胞介素-24啟動(dòng)子一道誘導(dǎo)抑癌基因的表達(dá)，進(jìn)而發(fā)揮抑癌作用。Kim等[42]還發(fā)現(xiàn)，miR-205與軸抑制基因（axis inhibitor，Axin）2的3'UTR（64～92）位點(diǎn)結(jié)合抑制Axin2基因表達(dá)，進(jìn)一步調(diào)控程序性細(xì)胞死亡過程和細(xì)胞毒性，而程序性細(xì)胞死亡和細(xì)胞毒性作用與腫瘤細(xì)胞的耐藥性密切相關(guān)。

研究[43]顯示，miR-205表達(dá)與EMT間存在著一定的關(guān)系，miR-205表達(dá)的降低會(huì)導(dǎo)致E-cad、神經(jīng)鈣黏素和纖連接蛋白表達(dá)下降，而EMT又常與腫瘤細(xì)胞耐藥相關(guān)。上調(diào)miR-205表達(dá)水平可以有效地逆轉(zhuǎn)腫瘤細(xì)胞EMT表型和抑制腫瘤細(xì)胞的侵襲遷移，進(jìn)一步提高腫瘤細(xì)胞對(duì)化學(xué)治療藥物的敏感性[44]。本課題組在前期研究中發(fā)現(xiàn)，miR-205在順鉑耐藥細(xì)胞株中表達(dá)下調(diào)，下調(diào)miR-205表達(dá)水平后可提高耐藥細(xì)胞對(duì)順鉑藥物的敏感性。

4　小結(jié)

miR-205在腫瘤化學(xué)治療耐藥的研究尚處起步階段，其具體的耐藥機(jī)制尚待進(jìn)一步闡明。但越來越多的研究表明，miR-205可與多個(gè)基因靶向結(jié)合調(diào)控腫瘤細(xì)胞的各種生命活動(dòng)，在參與腫瘤化學(xué)治療耐藥過程中發(fā)揮重要作用。研究[45]顯示，miR-205在鱗狀上皮的表達(dá)具有高度特異性，且在口腔癌中的表達(dá)水平較其他腫瘤組織高，在調(diào)控口腔癌腫瘤細(xì)胞增殖和程序性細(xì)胞死亡過程中起關(guān)鍵作用。miR-205在腫瘤化學(xué)治療耐藥中的研究?jī)r(jià)值不可估量，以miR-205為作用靶點(diǎn)，通過逆轉(zhuǎn)miR-205的表達(dá)水平可以有效地提高腫瘤細(xì)胞的化學(xué)治療敏感性。利用基因組學(xué)的方法分析患者的miRNA和mRNA表達(dá)譜，構(gòu)建以miR-205為藥物作用靶標(biāo)的新型化學(xué)治療藥物及個(gè)性化用藥，將為克服腫瘤化學(xué)治療耐藥開辟新的途徑。

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（本文采編 王晴）

Role of microRNA-205 on chemoresistance and its mechanism in tumor

Li Long, Huang Hongzhang.
(Dept. of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China)

This study was supported by the National Natural Science Foundation of China(81272949).

Resistance to chemotherapeutic drugs is a difficult problem that often leads to the failure of chemotherapy in tumor clinical treatment. Chemoresistance mechanism involves the complex and unclear regulation of multiple genes and signaling pathways. MicroRNA(miRNA) are endogenous, small non-coding, single-strand RNA molecules that are 18-25 nucleotides in length. They play a crucial role in regulating various cellular biological processes. Accumulated studies show that aberrant expression of miRNA is associated with progression, migration, and chemotherapy resistance in various cancers. Recently, an increasing number of studies reveal that miRNA-250(miR-205) participates in regulating chemotherapy resistance in cancers. However, the role of miR-205 in chemoresistance is still unclear. This paper reviews the relationship between miR-205 and chemotherapy resistance in tumors.

microRNA-205； tumor； chemoresistance

Q 786

A [doi] 10.7518/gjkq.2016.06.025

2016-02-11；

2016-07-04

國(guó)家自然科學(xué)基金（81272949）

李龍，主治醫(yī)師，博士，Email：k369_ll@126.com

黃洪章，教授，博士，Email：huanghongzhang@tom.com