miR-17-5p在腫瘤中作用的研究進展*

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）作為生物體內一種重要的基因調控分子，其異常表達與人類多種疾病密切相關。近年來，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已成為腫瘤學研究的新方向。miR-17-5p作為miR-17～92簇的一員，是近年來疾病研究的熱點，多種腫瘤發生發展中均有涉及。本文主要對miR-17-5p的基本特征及其在腫瘤中的作用進行綜述。

關鍵詞miR-17-5p腫瘤靶基因

作者單位：①大理大學臨床醫學院（云南省大理市671000）；②大理大學附屬醫院病理科

*本文課題受云南省高校科技創新團隊支持計劃項目（編號：云教科〔2014〕22號）資助

微小RNA（microRNA，miRNA）是一類由內源基因編碼的長度為19～25個核苷酸的非蛋白編碼單鏈RNA分子，在物種之間高度保守。miRNA通常可作用于一個或多個信使RNA（mRNA），并通過降解mRNA或抑制翻譯水平而達到負調控基因表達的目的。近年來，miRNA與腫瘤的關系已成為現階段研究的一個熱點。miRNA可作為腫瘤診斷、治療及預后的標志物。本文對miR-17-5p的特征及在腫瘤中的研究進展進行綜述。

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，該家族已被證實參與生物正常發育以及惡性腫瘤生長及死亡的關鍵途徑［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，在多種實體及血液系統腫瘤中高表達。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［3-4］。miR-17-5p是多順反子C13ORF25的一員，C13ORF25已被證明是由MYC蛋白的啟動子結合域上調的，并且在70%彌漫性大B細胞性淋巴瘤（dif?fuse large B-cell lymphoma，DLBCL）中過表達［5］。

2　miR-17-5p在腫瘤中的表達

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

3　miR-17-5p的靶基因

miR-17-5p主要是通過靶基因及相關信號通路等在腫瘤中發揮癌基因或抑癌基因的作用（表2），因此鑒別出miR-17-5p的靶基因對研究其功能至關重要。目前有很多預測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）數據庫分析靶基因功能。miR? NA主要通過降解mRNA或抑制翻譯水平負調控其靶基因。在大多數腫瘤中，miR-17-5p呈現上調趨勢，因此其靶基因缺失或下調。但是在Li等［4］的研究中發現，在卵巢癌中過表達miR-17-5p可通過作用于細胞周期G1/S期促進腫瘤細胞增殖、抑制凋亡，同時促進靶基因YES1的表達。敲除YES1基因能夠抑制細胞增殖、誘導細胞周期阻滯。

表1　miR-17-5p在腫瘤中的表達及作用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在腫瘤形成和發展中的作用

4.1miR-17-5p與腫瘤增殖和凋亡

miR-17-5p在細胞增殖G1/S期起著重要的作用，并且在此過程中調控20多個mRNA表達，其中有促進增殖的基因，也有抑制增殖的基因［49］。目前發現，miR-17-5p在大多數腫瘤中起到癌基因的作用，促進細胞增殖，抑制細胞凋亡。Wang等［23］利用鼠移植瘤模型，證實miR-17-5p在胃癌組織中高表達，并且負調控靶基因P21和TP53INP1，從而促進腫瘤細胞的增殖，抑制其凋亡。有研究發現，在子宮內膜癌細胞中轉染miR-17-5p模擬物或是P21小干擾RNA能夠逆轉化療藥物硼替佐米對子宮內膜癌細胞的增殖抑制和促進凋亡的作用［22］。

但在少部分關于前列腺癌、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］研究發現前列腺癌中miR-17-5p明顯下調，并且負調控靶基因PCAF，PCAF上調可促進雄激素受體轉錄活性以及癌細胞的生長。

4.2miR-17-5p與腫瘤的侵襲及轉移

Wei等［36］研究發現，miR-17-5p的表達在轉移性垂體腺癌中較原發性垂體腺瘤明顯上調，可負調控靶基因PTEN和TIMP2。也有研究通過構建肝細胞癌小鼠模型，證實miR-17-5p的上調可增加腫瘤細胞遷移率，血清中miR-17-5p的表達水平可作為非侵襲性肝細胞癌的生物標記物［6-7］。Tayebi等［8］研究發現，miR-17-5p在轉移性肝細胞癌中和非轉移性細胞癌中的表達存在差異。miR-17-5p的表達水平在非轉移性肝細胞癌活檢組織中較正常肝組織中明顯下調，而在轉移性肝細胞癌中高表達。在肝癌細胞株中過表達miR-17-5p能夠通過負調控靶基因E2F1和c-MYC促進腫瘤細胞的增殖、生長、侵襲及集落形成，拮抗miR-17-5p的表達則會出現相反的效果。

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

4.3miR-17-5p與腫瘤的化療耐藥性及預后

miR-17-5p的表達還與腫瘤細胞的化療耐藥性以及患者的總生存率、預后有關。Yan等［19］在胰腺癌中發現miR-17-5p高表達，并且負調控Bim從而降低吉西他濱的化療敏感性。Wu等［37］證實抑制miR-17-5p的表達能夠通過抑制P21增強口腔鱗癌細胞的輻射敏感度。在結直腸癌中miR-17-5p高表達，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［27］。Chen等［30］發現在肺癌患者的血清中miR-17-5p高表達，并且與肺癌患者的預后差相關。

Chatterjee等［33］發現，miR-17-5p在紫杉醇耐藥的肺癌細胞中較紫杉醇敏感的肺癌細胞中明顯下調，證實肺癌的紫杉醇耐藥性可能與miR-17-5p的低表達引起beclin上調有關。

5　展望

近幾年，由于各種原因，多種腫瘤發病率明顯增加，很多腫瘤患者直至疾病晚期才確診，大多數腫瘤現在仍無有效的治療方法，總體生存率較低［51- 53］。miR-17-5p屬于miR-17～92基因簇，該基因簇在實體癌以及血液學腫瘤中研究較多［54］，并且有研究發現，在某些癌癥中miR-17～92基因簇中的miR-17起主導作用［55］。目前miR-17-5p主要作為癌基因發揮作用。但是miR-17-5p可同時調控多個靶點mRNA，其中既有癌基因，也有抑癌基因［49］，因此miR-17-5p在腫瘤發病機制中的作用及其靶基因功能有待進一步深入研究，其作用機制必將為腫瘤診斷、治療和預后提供新的突破口。

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（2015-12-29收稿）

（2016-01-20修回）

（編輯：孫喜佳校對：鄭莉）

吳瑩瑩專業方向為頭頸部腫瘤的基礎與臨床研究。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

作者簡介

通信作者：潘云panyun09@163.com

doi:10.3969/j.issn.1000-8179.2016.03.491