miR-17-5p與消化系統(tǒng)腫瘤關系的研究進展

連嬌燕，金海，文國容，庹必光

(遵義醫(yī)學院附屬醫(yī)院，貴州遵義563003)

·綜述·

miR-17-5p與消化系統(tǒng)腫瘤關系的研究進展

連嬌燕，金海，文國容，庹必光

(遵義醫(yī)學院附屬醫(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，能促進消化系統(tǒng)腫瘤的惡性化演進，并與患者預后不良有關。血漿miR-17-5p表達水平可用于早期診斷消化系統(tǒng)腫瘤，并可評價患者預后。靶向抑制miR-17-5p表達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；預后

微小RNA(miRNA)是一類長度約為22個核苷酸的內(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，參與調(diào)控消化系統(tǒng)腫瘤的發(fā)生、發(fā)展。miR-17～92家族是第一個被發(fā)現(xiàn)與腫瘤相關的miRNA家族，可參與調(diào)控消化系統(tǒng)腫瘤的演進。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，尤其是消化系統(tǒng)腫瘤，如肝癌、胃癌、食管癌等。本文結(jié)合文獻就miR-17-5p與消化系統(tǒng)腫瘤關系的研究進展作一綜述。

1 miR-17-5p與肝癌的關系

miR-17-5p在肝癌組織中的異常表達與其惡性生物學行為及患者預后明顯相關。Peng等[2]研究發(fā)現(xiàn)，抑癌基因INTS6可競爭性結(jié)合miR-17-5p，對肝癌的發(fā)生起保護性作用。Tayebi等[3]研究證實，肝癌細胞Huh7過表達miR-17-5p既可促進肝癌細胞的增殖、生長、遷移，還可抑制抑癌基因E2F1的表達。Yang等[4]研究認為，miR-17-5p通過激活MAPK并誘導HSP27磷酸化，提高肝癌細胞的遷移能力。另外，miR-17-5p還可下調(diào)抑癌基因PTEN的表達；將miR-17-5p轉(zhuǎn)染肝癌細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]。以上研究說明miR-17-5p可促進肝癌細胞的增殖、遷移、侵襲等惡性生物學行為，促進肝癌的惡性化進展。Chen等[6]研究亦證實，在人類肝癌組織中miR-17-5p呈高表達，且其高表達與腫瘤病理分期差、血管侵襲強以及整體生存率或無病生存率低相關。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，但復發(fā)后miR-17-5p再次升高；提示miR-17-5p可作為判斷肝癌復發(fā)的分子標志物[8，9]。

2 miR-17-5p與結(jié)腸癌的關系

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

3 miR-17-5p與胰腺癌的關系

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，用miR-17-5p穩(wěn)定轉(zhuǎn)染胰腺癌細胞可增加癌細胞的增殖及侵襲能力。提示miR-17-5p高表達與胰腺癌的惡性程度及患者預后不良相關。Yan等[16]采用miR-17-5p抑制劑轉(zhuǎn)染胰腺癌細胞株Panc-1、BxPC-3，發(fā)現(xiàn)轉(zhuǎn)染后的胰腺癌細胞出現(xiàn)生長抑制、自發(fā)性凋亡，caspase-3活性和癌細胞對吉西他濱的敏感性明顯增強，且隨著miR-17-5p抑制劑用量的增加，促凋亡分子Bim表達明顯上調(diào)。說明miR-17-5p抑制劑可通過下調(diào)miR-17-5p表達，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高表達與腫瘤轉(zhuǎn)移和臨床分期相關。有研究證實，腫瘤干細胞(CSCs)參與調(diào)控胰腺癌的發(fā)生、發(fā)展以及對化療藥物的耐藥性[17]。Cioffi等[18]研究發(fā)現(xiàn)，胰腺癌CSCs過表達miR-17-5p可激活TGF-β家族中的NODAL/ACTIVIN/TGF-β1多重信號通路，靶向抑制p21、p57以及TBX3等基因表達，這一過程可降低胰腺癌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，但其具體機制目前仍不清楚。

4 miR-17-5p與胃癌的關系

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表達明顯升高，并在轉(zhuǎn)錄后通過調(diào)控p21、p53誘導核蛋白1表達，促進胃癌細胞增殖；而鼠雙微體2基因可上調(diào)胃癌組織miR-17-5p表達，并抑制p21表達，繼而促進其惡性行為[20]；促增殖基因細胞因子信號負性調(diào)控因子6(SOCS6)是miR-17-5p的靶基因，miR-17-5p通過抑制SOCS6的表達，促進胃癌細胞增殖[21]。以上研究證實，胃癌組織miR-17-5p高表達可促進其惡性行為。有學者還發(fā)現(xiàn)，胃癌細胞MKN-74亦高表達miR-17-5p，但腸球菌感染可下調(diào)該miRNA表達。提示胃癌細胞miR-17-5p表達改變可能與胃癌合并細菌感染相關[22]。Wang等[23]研究認為，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，而高表達miR-17-5p的胃癌患者整體生存率明顯降低。提示血漿miR-17-5p水平可用于評估胃癌患者的臨床分期和預后判斷。

綜上所述，miR-17-5p可促進消化系統(tǒng)腫瘤細胞增殖、遷移和侵襲，其高表達與患者預后不良有關。目前的研究主要集中于miR-17-5p對腫瘤生物學行為的影響以及對患者預后判斷的價值，對其在消化系統(tǒng)腫瘤中發(fā)揮促癌作用的具體機制及靶向miR-17-5p治療消化系統(tǒng)腫瘤的研究甚少。隨著分子生物學研究的進一步深入，miR-17-5p將在消化系統(tǒng)腫瘤的預防、早期診斷、個體化治療以及預后監(jiān)測方面發(fā)揮重要作用。

[1] Hausser J, Zavolan M. Identification and consequences of miRNA-target interactions--beyond repression of gene expression[J]. Nat Rev Genet, 2014,15(9):599-612.

[2] Peng H, Ishida M, Li L, et al. Pseudogene INTS6P1 regulates its cognate gene INTS6 through competitive binding of miR-17-5p in hepatocellular carcinoma[J]. Oncotarget, 2015,6(8):5666-5677.

[3] Tayebi HM, Omar K, Hegy S, et al. Repression of miR-17-5p with elevated expression of E2F-1 and c-MYC in non-metastatic hepatocellular carcinoma and enhancement of cell growth upon reversing this expression pattern[J]. Biochemical Biophys Res Commun, 2013,434(3):421-427.

[4] Yang F, Yin Y, Wang F, et al. miR-17-5p promotes migration of human hepatocellular carcinoma cells through the p38 mitogen-activated protein kinase-heat shock protein 27 pathway[J]. Hepatology, 2010,51(5):1614-1623.

[5] Shan SW, Fang L, Shatseva T, et al. Mature miR-17-5p and passenger miR-17-3p induce hepatocellular carcinoma by targeting PTEN, GalNT7 and vimentin in different signal pathways[J]. J Cell Sci, 2013,126(Pt 6):1517-1530.

[6] Chen L, Jiang M, Yuan W, et al. miR-17-5p as a novel prognostic marker for hepatocellular carcinoma[J]. J Invest Surg, 2012,25(3):156-161.

[7] Zheng J, Dong P, Gao S, et al. High expression of serum miR-17-5p associated with poor prognosis in patients with hepatocellular carcinoma[J]. Hepatogastroenterology, 2013,60(123):549-552.

[8] Jung YJ, Kim JW, Park SJ, et al. c-Myc-mediated overexpression of miR-17-92 suppresses replication of hepatitis B virus in human hepatoma cells[J]. J Med Virol, 2013,85(6):969-978.

[9] Oksuz Z, Serin MS, Kaplan E, et al. Serum microRNAs: miR-30c-5p, miR-223-3p, miR-302c-3p and miR-17-5p could be used as novel non-invasive biomarkers for HCV-positive cirrhosis and hepatocellular carcinoma[J]. Mol Biol Rep, 2015,42(3):713-720.

[10] Motoyama K, Inoue H, Takatsuno Y, et al. Over-and under-expressed microRNAs in human colorectal cancer[J]. Int J Oncol, 2009,34(4):1069-1075.

[11] Kara M, Yumrutas O, Ozcan O, et al. Differential expressions of cancer-associated genes and their regulatory miRNAs in colorectal carcinoma[J]. Gene, 2015,567(1):81-86.

[12] 常金榮，王建華，鄺棗園，等.從miRNA-17-92途徑探討小檗堿和吳茱萸堿對大腸癌HT29細胞周期調(diào)控機制[J].中藥藥理與臨床，2014，30(3)：19-22.

[13] Ling H, Spizzo R, Atlasi Y, et al. CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer[J]. Genome Res, 2013,23(9):1446-1461.

[14] Fang L, Li H, Wang L, et al. microRNA-17-5p promotes chemotherapeutic drug resistance and tumour metastasis of colorectal cancer by repressing PTEN expression[J]. Oncotarget, 2014,5(10):2974-2987.

[15] Yu J, Ohuchida K, Mizumoto K, et al. microRNA miR-17-5p is overexpressed in pancreatic cancer, associated with a poor prognosis, and involved in cancer cell proliferation and invasion[J]. Cancer Biol Ther, 2010,10(8):748-757.

[16] Yan HJ, Liu WS, Sun WH, et al. miR-17-5p inhibitor enhances chemosensitivity to gemcitabine via upregulating bim expression in pancreatic cancer cells[J]. Dig Dis Sci, 2012,57(12):3160-3167.

[17] Que R, Ding G, Chen J, et al. Analysis of serum exosomal microRNAs and clinicopathologic features of patients with pancreatic adenocarcinoma[J]. World J Surg Oncol, 2013(11):219.

[18] Cioffi M, Trabulo SM, Sanchez-Ripoll Y, et al. The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells[J]. Gut, 2015,64(12):1936-1948.

[19] Tsujiura M, Ichikawa D, Komatsu S, et al. Circulating microRNAs in plasma of patients with gastric cancers[J]. Br J Cancer, 2010,102(7):1174-1179.

[20] Wang M, Gu H, Qian H, et al. miR-17-5p/20a are important markers for gastric cancer and murine double minute 2 participates in their functional regulation[J]. Eur J Cancer, 2013,49(8):2010-2021.

[21] Wu Q, Luo G, Yang Z, et al. miR-17-5p promotes proliferation by targeting SOCS6 in gastric cancer cells[J]. FEBS Letters, 2014,588(12):2055-2062.

[22] Strickertsson JA, Rasmussen LJ, Friis-Hansen L. Enterococcus faecalis infection and reactive oxygen species down-regulates the miR-17-92 cluster in gastric adenocarcinoma cell culture[J]. Genes(Basel), 2014,5(3):726-738.

[23] Wang M, Gu H, Wang S, et al. Circulating miR-17-5p and miR-20a: molecular markers for gastric cancer[J]. Mol Med Rep, 2012,5(6):1514-1520.

國家自然科學基金資助項目(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)