劉紫玲，彭志平，史學(xué)森

(包頭市中心醫(yī)院 檢驗(yàn)科， 內(nèi)蒙古 包頭 014000)

胃癌相關(guān)miRNA的臨床應(yīng)用價(jià)值

劉紫玲，彭志平，史學(xué)森*

(包頭市中心醫(yī)院 檢驗(yàn)科， 內(nèi)蒙古 包頭 014000)

胃癌患者癌組織或外周血中某些表達(dá)異常的miRNA與胃癌發(fā)病機(jī)制即發(fā)生發(fā)展過程息息相關(guān)。一些特定的miRNA的表達(dá)水平可以提示胃癌的發(fā)生及所處階段、侵襲轉(zhuǎn)移能力及是否已經(jīng)發(fā)生了轉(zhuǎn)移、術(shù)后復(fù)發(fā)的可能性及患者的存活時(shí)間以及目前的化學(xué)藥物治療是否有效。

miRNA；胃癌；臨床應(yīng)用

MiRNA通常位于染色體區(qū)域的“脆性點(diǎn)”以及與腫瘤相關(guān)的基因區(qū)域，腫瘤患者表達(dá)水平發(fā)生變化的miRNA可以分為二類：抑癌作用的miRNA(tumor-suppressor-miRNA)和致癌作用的miRNA(tumor-onco-miRNA)，兩類miRNA的過表達(dá)(over-expression)與腫瘤的發(fā)生發(fā)展息息相關(guān)。過表達(dá)的Onco-miRNA/suppressor-miRNA可以更高水平的結(jié)合到其靶mRNA使其降解或者翻譯水平下降，從而起到致癌/抑癌的作用[1]。

胃癌(gastric carcinoma)是消化道系統(tǒng)常見的惡性腫瘤之一，占胃惡性腫瘤的95%，其病死率在癌癥患者中高居第2位。近年來國內(nèi)外在研究胃癌患者miRNA的表達(dá)時(shí)發(fā)現(xiàn)，胃癌的miRNA表達(dá)譜與胰腺直腸癌前列腺癌的miRNA表達(dá)譜存在相似性，但與乳腺癌和肺癌的不同。胃癌患者表達(dá)有顯著差異的起到致癌作用的miRNA，可調(diào)節(jié)胃癌細(xì)胞的增殖，遷移和侵襲能力，如：miR-150可下調(diào)抑癌基因EGR2的表達(dá)，miR-181a可下調(diào)抑癌基因KLF的表達(dá)，均可引起癌細(xì)胞的增殖。癌細(xì)胞能夠維持一定的增殖能力以后，還需要獲得其他相應(yīng)的能力，使其穿過上皮細(xì)胞基底細(xì)胞層進(jìn)入血液循環(huán)系統(tǒng)從而轉(zhuǎn)移至淋巴結(jié)以及更遠(yuǎn)的組織，實(shí)現(xiàn)癌擴(kuò)散轉(zhuǎn)移，如miR-650和miR-622與抑癌基因ING4結(jié)合，可增強(qiáng)胃癌的轉(zhuǎn)移和侵襲能力。

1 miRNA在胃癌臨床診斷中的作用

臨床上常將癌胚抗原(CEA)和癌抗原CA19-9，CA72-4腫瘤標(biāo)志物作為腫瘤篩查的工具，但其缺乏高度的特異性和敏感性。而miRNA的表達(dá)在胃癌早期已經(jīng)發(fā)生了變化，追蹤其表達(dá)圖譜的變化情況，能夠使臨床醫(yī)生更早的對胃癌做出診斷[2]。因而miRNA可能成為最有潛力的腫瘤診斷標(biāo)志物。胃鏡和活組織檢查是傳統(tǒng)的診斷胃癌的方法，但具有侵入性，檢查外周血中miRNA的表達(dá)日漸成為診斷胃癌的新方法，單一1條miRNA對癌癥的診斷意義不大而多個miRNA組合在一起構(gòu)成腫瘤特異性表達(dá)譜可高度特異地反應(yīng)腫瘤發(fā)展的階段差異，從而進(jìn)行更為全面的分析。

大量的研究發(fā)現(xiàn)，胃癌患者外周血的miRNA表達(dá)譜與正常人相比表達(dá)有顯著差異，其中:miR-1、miR-17、miR-25、miR-18a、miR-18b、miR-19a、miR-20a、miR-20b、miR-21、miR-27a、miR-34a、miR-34b、miR-34c、miR-98、miR-106a、miR-106b、miR-128a、miR-130b*、miR-138、miR-147、miR-181a-2*、miR-181b、miR-185、miR-196a*、miR-199a-3p、miR-221*、miR-223、miR-296-5p、miR-302f、miR-337-3p、miR-340*、miR-378、miR-421、miR-423-5p、miR-520c-3p、miR-575、miR-601、miR-616*、miR-658和miR-1259在胃癌患者外周血中的表達(dá)較正常人顯著升高，而let-7a、miR-128b、miR-129和miR-148降低[3-8]。且這些miRNA作為腫瘤標(biāo)志物的特異性較CEA和CA高。中國是胃癌高發(fā)的國家，高危人群若能夠通過miRNA的篩查提高胃癌早期的診斷率，非常有利于提高胃癌的治療效果。

2 miRNA在預(yù)后評估中的作用

臨床醫(yī)生想要做到準(zhǔn)確預(yù)測患者存活時(shí)間，疾病進(jìn)展，預(yù)后或者其對治療的反應(yīng)是非常有難度的。miRNA有潛力成為預(yù)測疾病結(jié)局的有力工具是由于其在組織，循環(huán)中表達(dá)的穩(wěn)定性和特異性。很多實(shí)驗(yàn)也證實(shí)了miRNA的差異表達(dá)與胃癌患者存活時(shí)間，疾病所處階段，腫瘤復(fù)發(fā)和淋巴結(jié)轉(zhuǎn)移緊密相關(guān)。例如：miR-21、miR-223、 miR-338、miR-7a、miR-30a-5p和miR-126[9]可預(yù)測患者所處階段，細(xì)胞學(xué)亞型，存活時(shí)間。國內(nèi)已發(fā)現(xiàn)并作報(bào)道的miRNA如表1[10-23]。

3 miRNA與化療

胃癌患者在治療過程中對化療藥物的抵抗性直接影響存活時(shí)間，通過檢測患者的miRNA的表達(dá)譜可以發(fā)現(xiàn)患者是否發(fā)生了對化療藥物產(chǎn)生了耐藥。例如[24]：胃癌組織中miR-508-5p高表達(dá)預(yù)示著胃癌患者發(fā)生了多重耐藥。胃癌組織中高表達(dá)let-7g、miR-342、miR-16、miR-181、miR-1和miR-34表明患者對化療藥物順鉑和5-氟尿嘧啶敏感，而當(dāng)miR-518f、miR-520a、miR-520d、miR-519e、miR-36和miR-517高表達(dá)意味著患者對其發(fā)生了耐藥，且當(dāng)轉(zhuǎn)染相應(yīng)基因，改變miRNA表達(dá)水平以后，可逆轉(zhuǎn)患者對化療藥物的耐藥狀態(tài)。

4 miRNA與治療方法

miRNA調(diào)節(jié)抑癌和致癌基因表達(dá)，是腫瘤發(fā)展進(jìn)程中的控制中心[25]，miRNA可調(diào)節(jié)蛋白表達(dá)影響多條信號途徑， 所以與編碼基因相比，miRNA作為腫瘤靶分子的療效更佳。當(dāng)前基于miRNA治療方案的基礎(chǔ)策略是采取基因敲除抑制或下調(diào)致癌miRNA的表達(dá)，如：應(yīng)用抑制miRNA的小分子藥物；遵循堿基配對原則，競爭性的阻斷其與靶基因的相互作用等。相反，針對抑癌miRNA(miR-433、miR-127、miR-129、miR-148a、miR-212、miR-1336和miR-202-3p等)則是采取轉(zhuǎn)進(jìn)外源的miRNA，提高其水平，從而獲得腫瘤治療的目的。

表1 國內(nèi)已發(fā)現(xiàn)的胃癌組織miRNA差異表達(dá)的預(yù)測作用Table 1 Gastric cancer with predictive role of miRNA in China

*代表在外周血的表達(dá)也已得到相同驗(yàn)證結(jié)果.

5 結(jié)語

miRNA參與腫瘤的發(fā)生發(fā)展的各個過程，經(jīng)過科學(xué)家不懈的努力，日后可能廣泛應(yīng)用于癌癥的早期診斷，預(yù)后和對放化療效果的檢測，成為新一代治療方法。但目前關(guān)于miRNA應(yīng)用與臨床的實(shí)驗(yàn)尚缺乏較高的可信度和確切的數(shù)據(jù)。對診斷而言：臨床需要統(tǒng)一的標(biāo)準(zhǔn)和檢測平臺。對治療而言：研究者需要設(shè)計(jì)出更好的無毒副作用的小分子藥物等等。所以，目前仍需要更多而深入的研究，提高臨床在診治胃癌時(shí)使用miRNA的可行性。

[1] 周玨宇,石嶸,鄭文嶺,等. microRNA 與腫瘤細(xì)胞周期的關(guān)系及其研究方法進(jìn)展[J].基礎(chǔ)醫(yī)學(xué)和臨床,2013,1:9-14.

[2] Liu H, Zhu L, Liu B,etal. Genome-wide microRNA profiles identify miR-378 as a serum biomarker for early detection of gastric cancer[J].Cancer Lett,2012,316:196-203.

[3] Tsujiura M, Ichikawa D, Komatsu S,etal. Circulating microRNAs in plasma of patients with gastric cancers[J].Br J Cancer, 2010,102:1174-1179.

[4] Li X, Zhang Y, Zhang Y,etal.Survival prediction of gastric cancer by a seven-microRNA signature[J].Gut,2010,59:579-585.

[5] Li J, Guo Y, Liang X,etal. MicroRNA-223 functions as an oncogene in human gastric cancer by targeting FBXW7/hCdc4[J]. Cancer Res Clin Oncol, 2012, 138:763-774.

[6] Kurashige J. Kamohara H. Watanabe M,etal. MicroRNA-200b Regulates Cell Proliferation, Invasion, and Migration by Directly Targeting ZEB2 in Gastric Carcinoma[J].Ann Surg Oncol,2012,19:656-664.

[7] Gao P, Xing AY, Zhou Y,etal. The molecular mechanism of microRNA-145 to suppress invasion-metastasis cascade in gastric cancer[J]. Oncogene, 2012, 61.

[8] Cho WC. MicroRNAs: Potential biomarkers for cancer diagnosis, prognosis and targets for therapy[J]. Int. J. Biochem. Cell Biol. 2010, 42:1273-1281.

[9] Zhang X, Yan Z, Zhang J,etal. Combination of hsa-miR-375 and hsa-miR-142-5p as a predictor for recurrence risk in gastric cancer patients following surgical resection[J].Ann Oncol,2011,22:2257-2266.

[10] Xiong X, Ren HZ, Li MH,etal.Down-regulated miRNA-214 induces a cell cycle G1arrest in gastric cancer cells by up-regulating the PTEN protein[J].Pathol Oncol Res,2011,17:931-937.

[11] Nishida N, Mimori K, Fabbri M,etal.MicroRNA-125a-5p is an independent prognostic factor in gastric cancer and inhibits the proliferation of human gastric cancer cells in combination with trastuzumab[J].Clin Cancer Res, 2011,17:2725-2733.

[12] Kogo R, Mimori K, Tanaka F,etal.Clinical significance of miR-146a in gastric cancer cases[J].Clin Cancer Res,2011,17:4277-4284.

[13] Zheng B, Liang L, Wang C,etal. MicroRNA-148a suppresses tumor cell invasion and metastasis by downregulating ROCK1 in gastric cancer[J]. Clin Cancer Res, 2011,17:7574-7583.

[14] Xu Y, Zhao F, Wang Z,etal. MicroRNA-335 acts as a metastasis suppressor in gastric cancer by targeting Bcl-w and specificity protein 1[J].Oncogene,2012,31:1398-1407.

[15] Sun T, Wang C, Xing J,etal. miR-429 modulates the expression of c-myc in human gastric carcinoma cells[J]. Eur J Cancer,2011,47:2552-2559.

[16] Brenner B, Hoshen MB, Purim O,etal. MicroRNAs as a potential prognostic factor in gastric cancer[J]. World J Gastroenterol, 2011,17:3976-3985.

[17] Liu K, Li G, Fan C,etal.Increased Expression of MicroRNA-221 in gastric cancer and its clinical significance[J].J Int Med Res,2012,40:467-474.

[18] Tseng CW, Lin CC, Chen CN,etal.Integrative network analysis reveals active microRNAs and their functions in gastric cancer[J]. BMC Syst Biol,2011,5:99.

[19] Li X, Zhang Y, Shi Y,etal.MicroRNA-107, an oncogene microRNA that regulates tumour invasion and metastasis by targeting DICER1 in gastric cancer[J].J Cell Mol Med,2011,15:1887-1895.

[20] Wang J, Zhang J, Wu J,etal.MicroRNA-610 inhibits the migration and invasion of gastric cancer cells by suppressing the expression of vasodilator-stimulated phosphoprotein[J].Eur J Cancer,2012,48:1904-1913.

[21] Kurashige J, Kamohara H, Watanabe M,etal.MicroRNA-200b regulates cell proliferation, invasion, and migration by directly targeting ZEB2 in gastric carcinoma[J].Ann Surg Oncol,2012,19,3:S656-S664.

[22] Zhao X, Dou W, He L,etal. MicroRNA-7 functions as an anti-metastatic microRNA in gastric cancer by targeting insulin-like growth factor-1 receptor[J]. Oncogene,2013,32:1363-1372.

[23] Kim CH, Kim HK, Rettig RL,etal.miRNA signature associated with outcome of gastric cancer patients following chemotherapy[J].BMC Med Genomics,2011,4:79.

[24] Shang Y, Zhang Z, Liu Z,etal. miR-508-5p regulates multidrug resistance of gastric cancer by targeting ABCB1 and ZNRD1[J].Oncogene, 2013,297:1-10.

[25] Lujambio A, Calin GA, Villanueva A,etal. A microRNA DNA methylation signature for human cancer metastasis[J]. Proc Natl Acad Sci USA, 2008,105:13556-13561.

Clinical application value of gastric carcinoma relevant miRNA

LIU Zi-ling, PENG Zhi-ping, SHI Xue-sen*

(Dept. of Clinical Laboratory, Baotou Central Hospital, Baotou 014000,China)

Specific miRNA in gastric cancer tissue or peripheral blood plasma played an important role in the pathogenesis of gastric carcinoma including occurrence and development. Some specific miRNA expression level could prompt the occurrence and stages of gastric cancer, invasion and metastasis ability and whether metastasis has occurred, the possibility of postoperative recurrence and survival time of patients as well as whether the chemical drug treatment is effective.

miRNA; gastric carcinoma; clinical application

2013-10-08

2013-11-22

*通信作者(correspondingauthor)： shixuesen1962@163.com

1001-6325(2014)04-0566-04

短篇綜述

R 73-3

A