連嬌燕，金海，文國(guó)容，庹必光

(遵義醫(yī)學(xué)院附屬醫(yī)院，貴州遵義563003)

·綜述·

miR-17-5p與消化系統(tǒng)腫瘤關(guān)系的研究進(jìn)展

連嬌燕，金海，文國(guó)容，庹必光

(遵義醫(yī)學(xué)院附屬醫(yī)院，貴州遵義563003)

miR-17-5p是miR-17～92家族的核心成員，是消化系統(tǒng)腫瘤的促癌miRNA之一。miR-17-5p可在肝癌、結(jié)腸癌、胰腺癌等消化系統(tǒng)腫瘤中高表達(dá)，能促進(jìn)消化系統(tǒng)腫瘤的惡性化演進(jìn)，并與患者預(yù)后不良有關(guān)。血漿miR-17-5p表達(dá)水平可用于早期診斷消化系統(tǒng)腫瘤，并可評(píng)價(jià)患者預(yù)后。靶向抑制miR-17-5p表達(dá)可為臨床治療消化系統(tǒng)腫瘤提供新的策略。

消化系統(tǒng)腫瘤；miR-17-5p；靶向治療；預(yù)后

微小RNA(miRNA)是一類(lèi)長(zhǎng)度約為22個(gè)核苷酸的內(nèi)源性非編碼RNA，可靶向調(diào)控多種癌基因或抑癌基因的表達(dá)，參與調(diào)控消化系統(tǒng)腫瘤的發(fā)生、發(fā)展。miR-17～92家族是第一個(gè)被發(fā)現(xiàn)與腫瘤相關(guān)的miRNA家族，可參與調(diào)控消化系統(tǒng)腫瘤的演進(jìn)。miR-17～92家族成員包括miR-17-5p、miR-17-3p、miR-18a、miR-19a、miR-19b、miR-20a以及miR-92-1[1]。miR-17-5p是該家族的核心成員，可在多種惡性腫瘤組織中異常表達(dá)，尤其是消化系統(tǒng)腫瘤，如肝癌、胃癌、食管癌等。本文結(jié)合文獻(xiàn)就miR-17-5p與消化系統(tǒng)腫瘤關(guān)系的研究進(jìn)展作一綜述。

1 miR-17-5p與肝癌的關(guān)系

miR-17-5p在肝癌組織中的異常表達(dá)與其惡性生物學(xué)行為及患者預(yù)后明顯相關(guān)。Peng等[2]研究發(fā)現(xiàn)，抑癌基因INTS6可競(jìng)爭(zhēng)性結(jié)合miR-17-5p，對(duì)肝癌的發(fā)生起保護(hù)性作用。Tayebi等[3]研究證實(shí)，肝癌細(xì)胞Huh7過(guò)表達(dá)miR-17-5p既可促進(jìn)肝癌細(xì)胞的增殖、生長(zhǎng)、遷移，還可抑制抑癌基因E2F1的表達(dá)。Yang等[4]研究認(rèn)為，miR-17-5p通過(guò)激活MAPK并誘導(dǎo)HSP27磷酸化，提高肝癌細(xì)胞的遷移能力。另外，miR-17-5p還可下調(diào)抑癌基因PTEN的表達(dá)；將miR-17-5p轉(zhuǎn)染肝癌細(xì)胞并移植到裸鼠皮下成瘤，可使瘤體體積更大，血管更豐富[5]。以上研究說(shuō)明miR-17-5p可促進(jìn)肝癌細(xì)胞的增殖、遷移、侵襲等惡性生物學(xué)行為，促進(jìn)肝癌的惡性化進(jìn)展。Chen等[6]研究亦證實(shí)，在人類(lèi)肝癌組織中miR-17-5p呈高表達(dá)，且其高表達(dá)與腫瘤病理分期差、血管侵襲強(qiáng)以及整體生存率或無(wú)病生存率低相關(guān)。Zheng等[7]研究發(fā)現(xiàn)，肝癌患者術(shù)前血清miR-17-5p維持在高水平，手術(shù)后血清miR-17-5p水平下降，但復(fù)發(fā)后miR-17-5p再次升高；提示miR-17-5p可作為判斷肝癌復(fù)發(fā)的分子標(biāo)志物[8，9]。

2 miR-17-5p與結(jié)腸癌的關(guān)系

研究發(fā)現(xiàn)，miR-17-5p在結(jié)腸癌組織中表達(dá)明顯上調(diào)。miR-17-5p及其靶基因E2F1參與調(diào)控結(jié)腸癌的發(fā)生并促進(jìn)細(xì)胞增殖，其異常高表達(dá)與患者預(yù)后不良相關(guān)[10]。Kara等[11]研究認(rèn)為，miR-17-5p可通過(guò)上調(diào)侏儒相關(guān)轉(zhuǎn)錄因子1而促進(jìn)結(jié)腸癌的發(fā)生、發(fā)展。miR-17-5p還可通過(guò)抑制E2F1的表達(dá)，促進(jìn)結(jié)腸癌細(xì)胞HT-29增殖；采用鹽酸小檗堿或吳茱萸堿干預(yù)HT-29細(xì)胞可靶向下調(diào)miR-17-5p的表達(dá)，將細(xì)胞周期阻遏在S期，從而抑制HT-29細(xì)胞的增殖[12]。提示miR-17-5p可促進(jìn)結(jié)腸癌細(xì)胞增殖，藥物干預(yù)miR-17-5p表達(dá)可靶向治療結(jié)腸癌。另外，作為長(zhǎng)鏈非編碼RNA的CCAT2，可通過(guò)上調(diào)結(jié)腸癌組織中miR-17-5p的表達(dá)，促進(jìn)腫瘤的生長(zhǎng)、轉(zhuǎn)移[13]。說(shuō)明miR-17-5p與結(jié)腸癌的預(yù)后相關(guān)，F(xiàn)ang等[14]研究亦證實(shí)此觀點(diǎn)。

3 miR-17-5p與胰腺癌的關(guān)系

Yu等[15]研究發(fā)現(xiàn)，在胰腺癌組織中miR-17-5p同樣呈高表達(dá)，用miR-17-5p穩(wěn)定轉(zhuǎn)染胰腺癌細(xì)胞可增加癌細(xì)胞的增殖及侵襲能力。提示miR-17-5p高表達(dá)與胰腺癌的惡性程度及患者預(yù)后不良相關(guān)。Yan等[16]采用miR-17-5p抑制劑轉(zhuǎn)染胰腺癌細(xì)胞株P(guān)anc-1、BxPC-3，發(fā)現(xiàn)轉(zhuǎn)染后的胰腺癌細(xì)胞出現(xiàn)生長(zhǎng)抑制、自發(fā)性凋亡，caspase-3活性和癌細(xì)胞對(duì)吉西他濱的敏感性明顯增強(qiáng)，且隨著miR-17-5p抑制劑用量的增加，促凋亡分子Bim表達(dá)明顯上調(diào)。說(shuō)明miR-17-5p抑制劑可通過(guò)下調(diào)miR-17-5p表達(dá)，抑制胰腺癌的惡性轉(zhuǎn)化。Que等[17]研究發(fā)現(xiàn)，胰腺癌患者血清miR-17-5p水平明顯高于胰腺良性腫瘤以及慢性胰腺炎患者，且胰腺癌組織miR-17-5p高表達(dá)與腫瘤轉(zhuǎn)移和臨床分期相關(guān)。有研究證實(shí)，腫瘤干細(xì)胞(CSCs)參與調(diào)控胰腺癌的發(fā)生、發(fā)展以及對(duì)化療藥物的耐藥性[17]。Cioffi等[18]研究發(fā)現(xiàn)，胰腺癌CSCs過(guò)表達(dá)miR-17-5p可激活TGF-β家族中的NODAL/ACTIVIN/TGF-β1多重信號(hào)通路，靶向抑制p21、p57以及TBX3等基因表達(dá)，這一過(guò)程可降低胰腺癌CSCs的自我更新能力、在體成瘤能力以及耐藥性。此為胰腺癌的靶向治療提供了新線索，但其具體機(jī)制目前仍不清楚。

4 miR-17-5p與胃癌的關(guān)系

研究發(fā)現(xiàn)，胃癌患者血漿miR-17-5p維持在高水平[19]；胃癌組織miR-17-5p表達(dá)明顯升高，并在轉(zhuǎn)錄后通過(guò)調(diào)控p21、p53誘導(dǎo)核蛋白1表達(dá)，促進(jìn)胃癌細(xì)胞增殖；而鼠雙微體2基因可上調(diào)胃癌組織miR-17-5p表達(dá)，并抑制p21表達(dá)，繼而促進(jìn)其惡性行為[20]；促增殖基因細(xì)胞因子信號(hào)負(fù)性調(diào)控因子6(SOCS6)是miR-17-5p的靶基因，miR-17-5p通過(guò)抑制SOCS6的表達(dá)，促進(jìn)胃癌細(xì)胞增殖[21]。以上研究證實(shí)，胃癌組織miR-17-5p高表達(dá)可促進(jìn)其惡性行為。有學(xué)者還發(fā)現(xiàn)，胃癌細(xì)胞MKN-74亦高表達(dá)miR-17-5p，但腸球菌感染可下調(diào)該miRNA表達(dá)。提示胃癌細(xì)胞miR-17-5p表達(dá)改變可能與胃癌合并細(xì)菌感染相關(guān)[22]。Wang等[23]研究認(rèn)為，胃癌患者血漿miR-17-5p水平與腫瘤組織分化程度低、腫瘤臨床分期高有關(guān)，而高表達(dá)miR-17-5p的胃癌患者整體生存率明顯降低。提示血漿miR-17-5p水平可用于評(píng)估胃癌患者的臨床分期和預(yù)后判斷。

綜上所述，miR-17-5p可促進(jìn)消化系統(tǒng)腫瘤細(xì)胞增殖、遷移和侵襲，其高表達(dá)與患者預(yù)后不良有關(guān)。目前的研究主要集中于miR-17-5p對(duì)腫瘤生物學(xué)行為的影響以及對(duì)患者預(yù)后判斷的價(jià)值，對(duì)其在消化系統(tǒng)腫瘤中發(fā)揮促癌作用的具體機(jī)制及靶向miR-17-5p治療消化系統(tǒng)腫瘤的研究甚少。隨著分子生物學(xué)研究的進(jìn)一步深入，miR-17-5p將在消化系統(tǒng)腫瘤的預(yù)防、早期診斷、個(gè)體化治療以及預(yù)后監(jiān)測(cè)方面發(fā)揮重要作用。

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國(guó)家自然科學(xué)基金資助項(xiàng)目(81360311)。

庹必光(E-mail： tuobiguang@aliyun.com)

10.3969/j.issn.1002-266X.2016.24.039

R735

A

1002-266X(2016)24-0101-03

2015-09-05)