miR-17-5p在腫瘤中作用的研究進(jìn)展*

吳瑩瑩　高波　丁躍明　綜述　潘云　審校

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miR-17-5p在腫瘤中作用的研究進(jìn)展*

吳瑩瑩①高波②丁躍明②綜述潘云②審校

摘要微小RNA（microRNA，miRNA）作為生物體內(nèi)一種重要的基因調(diào)控分子，其異常表達(dá)與人類多種疾病密切相關(guān)。近年來(lái)，miRNA在多種腫瘤中起著抑癌基因或是致癌基因的作用，因此，miRNA已成為腫瘤學(xué)研究的新方向。miR-17-5p作為miR-17～92簇的一員，是近年來(lái)疾病研究的熱點(diǎn)，多種腫瘤發(fā)生發(fā)展中均有涉及。本文主要對(duì)miR-17-5p的基本特征及其在腫瘤中的作用進(jìn)行綜述。

關(guān)鍵詞miR-17-5p腫瘤靶基因

作者單位：①大理大學(xué)臨床醫(yī)學(xué)院（云南省大理市671000）；②大理大學(xué)附屬醫(yī)院病理科

*本文課題受云南省高校科技創(chuàng)新團(tuán)隊(duì)支持計(jì)劃項(xiàng)目（編號(hào)：云教科〔2014〕22號(hào)）資助

微小RNA（microRNA，miRNA）是一類由內(nèi)源基因編碼的長(zhǎng)度為19～25個(gè)核苷酸的非蛋白編碼單鏈RNA分子，在物種之間高度保守。miRNA通常可作用于一個(gè)或多個(gè)信使RNA（mRNA），并通過(guò)降解mRNA或抑制翻譯水平而達(dá)到負(fù)調(diào)控基因表達(dá)的目的。近年來(lái)，miRNA與腫瘤的關(guān)系已成為現(xiàn)階段研究的一個(gè)熱點(diǎn)。miRNA可作為腫瘤診斷、治療及預(yù)后的標(biāo)志物。本文對(duì)miR-17-5p的特征及在腫瘤中的研究進(jìn)展進(jìn)行綜述。

1　miR-17-5p的基本特征

miR-17-5p屬于miR-17家族，其家族成員還包括miR-20a/b、miR-106a/b和miR-93，該家族已被證實(shí)參與生物正常發(fā)育以及惡性腫瘤生長(zhǎng)及死亡的關(guān)鍵途徑［1］。miR-17-5p屬于miR-17～92基因簇，該基因簇成員有miR-17、miR-18a、miR-19a、miR-19b、miR-20a、miR-92a，在多種實(shí)體及血液系統(tǒng)腫瘤中高表達(dá)。miR-17-5p位于人類13q31和嚙齒類14qE4染色體上［2］，可直接作用于mRNA的3'端的非編碼區(qū)［3-4］。miR-17-5p是多順?lè)醋覥13ORF25的一員，C13ORF25已被證明是由MYC蛋白的啟動(dòng)子結(jié)合域上調(diào)的，并且在70%彌漫性大B細(xì)胞性淋巴瘤（dif?fuse large B-cell lymphoma，DLBCL）中過(guò)表達(dá)［5］。

2　miR-17-5p在腫瘤中的表達(dá)

miR-17-5p在多種腫瘤中表達(dá)，與腫瘤細(xì)胞的增殖、凋亡、淋巴轉(zhuǎn)移及化療耐藥性等相關(guān)（表1）。不同組織來(lái)源或不同類型的腫瘤都具有特異性的mi?croRNA表達(dá)譜，但是同一腫瘤的microRNA表達(dá)譜在發(fā)生發(fā)展的不同分期階段也可能存在差異。miR-17-5p在大多數(shù)腫瘤中呈現(xiàn)上調(diào)趨勢(shì)，發(fā)揮著癌基因的作用。但對(duì)于少部分腫瘤，不同研究中miR-17-5p呈現(xiàn)不同的表達(dá)。

3　miR-17-5p的靶基因

miR-17-5p主要是通過(guò)靶基因及相關(guān)信號(hào)通路等在腫瘤中發(fā)揮癌基因或抑癌基因的作用（表2），因此鑒別出miR-17-5p的靶基因?qū)ρ芯科涔δ苤陵P(guān)重要。目前有很多預(yù)測(cè)miRNA靶基因的軟件，其中以miRWalk、Targetscan、miRanda等比較常用，并且可以利用GO（gene ontology）和KEGG（kyoto encyclopedia of genes and genomes）數(shù)據(jù)庫(kù)分析靶基因功能。miR? NA主要通過(guò)降解mRNA或抑制翻譯水平負(fù)調(diào)控其靶基因。在大多數(shù)腫瘤中，miR-17-5p呈現(xiàn)上調(diào)趨勢(shì)，因此其靶基因缺失或下調(diào)。但是在Li等［4］的研究中發(fā)現(xiàn)，在卵巢癌中過(guò)表達(dá)miR-17-5p可通過(guò)作用于細(xì)胞周期G1/S期促進(jìn)腫瘤細(xì)胞增殖、抑制凋亡，同時(shí)促進(jìn)靶基因YES1的表達(dá)。敲除YES1基因能夠抑制細(xì)胞增殖、誘導(dǎo)細(xì)胞周期阻滯。

表1　miR-17-5p在腫瘤中的表達(dá)及作用Table 1　The expression and functions of miR-17-5p in tumors

表2　miR-17-5p的靶基因Table 2　The target genes of miR-17-5p

4　miR-17-5p在腫瘤形成和發(fā)展中的作用

4.1miR-17-5p與腫瘤增殖和凋亡

miR-17-5p在細(xì)胞增殖G1/S期起著重要的作用，并且在此過(guò)程中調(diào)控20多個(gè)mRNA表達(dá)，其中有促進(jìn)增殖的基因，也有抑制增殖的基因［49］。目前發(fā)現(xiàn)，miR-17-5p在大多數(shù)腫瘤中起到癌基因的作用，促進(jìn)細(xì)胞增殖，抑制細(xì)胞凋亡。Wang等［23］利用鼠移植瘤模型，證實(shí)miR-17-5p在胃癌組織中高表達(dá)，并且負(fù)調(diào)控靶基因P21和TP53INP1，從而促進(jìn)腫瘤細(xì)胞的增殖，抑制其凋亡。有研究發(fā)現(xiàn)，在子宮內(nèi)膜癌細(xì)胞中轉(zhuǎn)染miR-17-5p模擬物或是P21小干擾RNA能夠逆轉(zhuǎn)化療藥物硼替佐米對(duì)子宮內(nèi)膜癌細(xì)胞的增殖抑制和促進(jìn)凋亡的作用［22］。

但在少部分關(guān)于前列腺癌、宮頸癌、乳腺癌等腫瘤的研究中，miR-17-5p則作為抑癌基因起作用。Gong等［14］研究發(fā)現(xiàn)前列腺癌中miR-17-5p明顯下調(diào)，并且負(fù)調(diào)控靶基因PCAF，PCAF上調(diào)可促進(jìn)雄激素受體轉(zhuǎn)錄活性以及癌細(xì)胞的生長(zhǎng)。

4.2miR-17-5p與腫瘤的侵襲及轉(zhuǎn)移

Wei等［36］研究發(fā)現(xiàn)，miR-17-5p的表達(dá)在轉(zhuǎn)移性垂體腺癌中較原發(fā)性垂體腺瘤明顯上調(diào)，可負(fù)調(diào)控靶基因PTEN和TIMP2。也有研究通過(guò)構(gòu)建肝細(xì)胞癌小鼠模型，證實(shí)miR-17-5p的上調(diào)可增加腫瘤細(xì)胞遷移率，血清中miR-17-5p的表達(dá)水平可作為非侵襲性肝細(xì)胞癌的生物標(biāo)記物［6-7］。Tayebi等［8］研究發(fā)現(xiàn)，miR-17-5p在轉(zhuǎn)移性肝細(xì)胞癌中和非轉(zhuǎn)移性細(xì)胞癌中的表達(dá)存在差異。miR-17-5p的表達(dá)水平在非轉(zhuǎn)移性肝細(xì)胞癌活檢組織中較正常肝組織中明顯下調(diào)，而在轉(zhuǎn)移性肝細(xì)胞癌中高表達(dá)。在肝癌細(xì)胞株中過(guò)表達(dá)miR-17-5p能夠通過(guò)負(fù)調(diào)控靶基因E2F1和c-MYC促進(jìn)腫瘤細(xì)胞的增殖、生長(zhǎng)、侵襲及集落形成，拮抗miR-17-5p的表達(dá)則會(huì)出現(xiàn)相反的效果。

Fan等［50］證實(shí)在乳腺癌細(xì)胞中抑制miR-17-5p能增加細(xì)胞轉(zhuǎn)移特性，加速原位異種移植瘤向肺部轉(zhuǎn)移，在瘤內(nèi)注射miR-17-5p模擬物能明顯減輕腫瘤的肺轉(zhuǎn)移。

4.3miR-17-5p與腫瘤的化療耐藥性及預(yù)后

miR-17-5p的表達(dá)還與腫瘤細(xì)胞的化療耐藥性以及患者的總生存率、預(yù)后有關(guān)。Yan等［19］在胰腺癌中發(fā)現(xiàn)miR-17-5p高表達(dá)，并且負(fù)調(diào)控Bim從而降低吉西他濱的化療敏感性。Wu等［37］證實(shí)抑制miR-17-5p的表達(dá)能夠通過(guò)抑制P21增強(qiáng)口腔鱗癌細(xì)胞的輻射敏感度。在結(jié)直腸癌中miR-17-5p高表達(dá)，并且靶向作用于P130，隨后激活Wnt/β-catenin通路，與患者總生存率降低有關(guān)［27］。Chen等［30］發(fā)現(xiàn)在肺癌患者的血清中miR-17-5p高表達(dá)，并且與肺癌患者的預(yù)后差相關(guān)。

Chatterjee等［33］發(fā)現(xiàn)，miR-17-5p在紫杉醇耐藥的肺癌細(xì)胞中較紫杉醇敏感的肺癌細(xì)胞中明顯下調(diào)，證實(shí)肺癌的紫杉醇耐藥性可能與miR-17-5p的低表達(dá)引起beclin上調(diào)有關(guān)。

5　展望

近幾年，由于各種原因，多種腫瘤發(fā)病率明顯增加，很多腫瘤患者直至疾病晚期才確診，大多數(shù)腫瘤現(xiàn)在仍無(wú)有效的治療方法，總體生存率較低［51- 53］。miR-17-5p屬于miR-17～92基因簇，該基因簇在實(shí)體癌以及血液學(xué)腫瘤中研究較多［54］，并且有研究發(fā)現(xiàn)，在某些癌癥中miR-17～92基因簇中的miR-17起主導(dǎo)作用［55］。目前miR-17-5p主要作為癌基因發(fā)揮作用。但是miR-17-5p可同時(shí)調(diào)控多個(gè)靶點(diǎn)mRNA，其中既有癌基因，也有抑癌基因［49］，因此miR-17-5p在腫瘤發(fā)病機(jī)制中的作用及其靶基因功能有待進(jìn)一步深入研究，其作用機(jī)制必將為腫瘤診斷、治療和預(yù)后提供新的突破口。

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（2015-12-29收稿）

（2016-01-20修回）

（編輯：孫喜佳校對(duì)：鄭莉）

吳瑩瑩專業(yè)方向?yàn)轭^頸部腫瘤的基礎(chǔ)與臨床研究。E-mail：wuyingying0105@126.com

Research progress on miR-17-5p in tumors

Yingying WU1, Bo GAO2, Yueming DING2, Yun PAN2
Correspondence to: Yun PAN; E-mail: panyun09@163.com
1College of Clinical Medicine, Dali University, Dali 671000, China;2Department of Pathology, Affiliated Hospital of Dali University, Dali 671000, China
This work was supported by the Program for Innovative Research Team (in Science and Technology) in the University of Yunnan Province (No. Yun Jiao Ke [2014] 22)

AbstractAs an important gene regulatory molecule, microRNA is closely related with various human diseases. Numerous studies have confirmed that microRNAs function as tumor suppressors or oncogenes in various tumor types. Therefore, microRNA investigation has become a new direction in oncology research. As a member of the miR-17 to -92 cluster, miR-17-5p has been the focus of research recently. MicroRNA is involved in many aspects of diseases, such as diabetes mellitus, endometriosis, and a variety of tumors. In this review, the basic characteristics and roles of miR-17-5p in tumors are elaborated.

Keywords:miR-17-5p, tumor, target gene

作者簡(jiǎn)介

通信作者：潘云panyun09@163.com

doi:10.3969/j.issn.1000-8179.2016.03.491