胃癌相關miRNA的臨床應用價值

劉紫玲，彭志平，史學森

(包頭市中心醫(yī)院 檢驗科， 內蒙古 包頭 014000)

胃癌相關miRNA的臨床應用價值

劉紫玲，彭志平，史學森*

(包頭市中心醫(yī)院 檢驗科， 內蒙古 包頭 014000)

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

miRNA；胃癌；臨床應用

MiRNA通常位于染色體區(qū)域的“脆性點”以及與腫瘤相關的基因區(qū)域，腫瘤患者表達水平發(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(over-expression)與腫瘤的發(fā)生發(fā)展息息相關。過表達的Onco-miRNA/suppressor-miRNA可以更高水平的結合到其靶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。近年來國內外在研究胃癌患者miRNA的表達時發(fā)現，胃癌的miRNA表達譜與胰腺直腸癌前列腺癌的miRNA表達譜存在相似性，但與乳腺癌和肺癌的不同。胃癌患者表達有顯著差異的起到致癌作用的miRNA，可調節(jié)胃癌細胞的增殖，遷移和侵襲能力，如：miR-150可下調抑癌基因EGR2的表達，miR-181a可下調抑癌基因KLF的表達，均可引起癌細胞的增殖。癌細胞能夠維持一定的增殖能力以后，還需要獲得其他相應的能力，使其穿過上皮細胞基底細胞層進入血液循環(huán)系統(tǒng)從而轉移至淋巴結以及更遠的組織，實現癌擴散轉移，如miR-650和miR-622與抑癌基因ING4結合，可增強胃癌的轉移和侵襲能力。

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的表達在胃癌早期已經發(fā)生了變化，追蹤其表達圖譜的變化情況，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組合在一起構成腫瘤特異性表達譜可高度特異地反應腫瘤發(fā)展的階段差異，從而進行更為全面的分析。

大量的研究發(fā)現，胃癌患者外周血的miRNA表達譜與正常人相比表達有顯著差異，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在預后評估中的作用

臨床醫(yī)生想要做到準確預測患者存活時間，疾病進展，預后或者其對治療的反應是非常有難度的。miRNA有潛力成為預測疾病結局的有力工具是由于其在組織，循環(huán)中表達的穩(wěn)定性和特異性。很多實驗也證實了miRNA的差異表達與胃癌患者存活時間，疾病所處階段，腫瘤復發(fā)和淋巴結轉移緊密相關。例如：miR-21、miR-223、 miR-338、miR-7a、miR-30a-5p和miR-126[9]可預測患者所處階段，細胞學亞型，存活時間。國內已發(fā)現并作報道的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間，通過檢測患者的miRNA的表達譜可以發(fā)現患者是否發(fā)生了對化療藥物產生了耐藥。例如[24]：胃癌組織中miR-508-5p高表達預示著胃癌患者發(fā)生了多重耐藥。胃癌組織中高表達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miR-518f、miR-520a、miR-520d、miR-519e、miR-36和miR-517高表達意味著患者對其發(fā)生了耐藥，且當轉染相應基因，改變miRNA表達水平以后，可逆轉患者對化療藥物的耐藥狀態(tài)。

4 miRNA與治療方法

miRNA調節(jié)抑癌和致癌基因表達，是腫瘤發(fā)展進程中的控制中心[25]，miRNA可調節(jié)蛋白表達影響多條信號途徑， 所以與編碼基因相比，miRNA作為腫瘤靶分子的療效更佳。當前基于miRNA治療方案的基礎策略是采取基因敲除抑制或下調致癌miRNA的表達，如：應用抑制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)則是采取轉進外源的miRNA，提高其水平，從而獲得腫瘤治療的目的。

表1 國內已發(fā)現的胃癌組織miRNA差異表達的預測作用Table 1 Gastric cancer with predictive role of miRNA in China

*代表在外周血的表達也已得到相同驗證結果.

5 結語

miRNA參與腫瘤的發(fā)生發(fā)展的各個過程，經過科學家不懈的努力，日后可能廣泛應用于癌癥的早期診斷，預后和對放化療效果的檢測，成為新一代治療方法。但目前關于miRNA應用與臨床的實驗尚缺乏較高的可信度和確切的數據。對診斷而言：臨床需要統(tǒng)一的標準和檢測平臺。對治療而言：研究者需要設計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使用miRNA的可行性。

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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