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microRNA—21在食管癌中的研究进展

2017-08-04杨鲸蓉吴波

中国医药导报 2017年16期
关键词:唾液靶点食管癌

杨鲸蓉++++++吴波

[摘要] 食管癌是我国常见的消化系统恶性肿瘤之一。食管癌具体发病机制尚不清楚。 microRNA是一类内源性非编码蛋白短链RNA,参与调控细胞增殖、分化、凋亡、耐药和侵袭转移等多种生物学行为。其中miR-21最受关注。miR-21在食管癌细胞或组织中高表达,发挥着类似于癌基因的作用。miR-21通过对靶基因的调控,参与食管癌细胞增殖、凋亡、侵袭、耐药和转移等过程。通过抑制miR-21的表达或阻碍miR-21与靶基因的相互作用在食管癌治疗中具有良好的应用前景。本文就miR-21在食管癌中的研究进展进行综述。

[关键词] microRNA-21;食管癌;生物学行为;预后

[中图分类号] R735.1 [文献标识码] A [文章编号] 1673-7210(2017)06(a)-0040-04

Advances research of microRNA-21 in esophageal cancer

YANG Jingrong1 WU Bo2▲

1.Department of Thoracic and Cardiovascular Surgery, Fuzhou General Hospital of Nanjing Military Command, Fujian Province, Fuzhou 350025, China; 2.Department of Emergency, Fuzhou General Hospital of Nanjing Military Command, Fujian Province, Fuzhou 350025, China

[Abstract] Esophageal cancer is one of the most common digestive system neoplasms in China. The mechanism of esophageal cancer is still unclear. microRNA is a kind of endogenous non-coding short RNA, which regulates many tumor biological behaviors,such as cell multiplication, differentiation, apoptosis, drug resistance and invasion. miR-21 is valued highly in miRNA. It express highly in esophageal cancer cell and tissue. miR-21 participates in esophageal cancer cell multiplication, differentiation, apoptosis, drug resistance and metastasis via regulating gene expression. This review summarizes the advances in research on miR-21 in esophageal cancer .

[Key words] MicroRNA-21; Esophageal cancer; Biological behaviors; Prognosis

食管癌是常見的消化道恶性肿瘤之一,在我国,食管癌的发病率居各类恶性肿瘤的第五位,死亡率居第四位。我国食管癌的发病人数和死亡人数占世界食管癌患者的50%以上。食管癌的发生和发展是一个多基因、多因素及多步骤的过程。microRNA(miRNA,miR)是一类内生的非蛋白编码的小RNA,长约21~23个核苷酸序列。其作为致癌因子或抑制因子参与肿瘤发生和发展的各个过程。miR-21是一种原癌miRNA,在多种恶性肿瘤中高表达,参与调控肿瘤细胞的多种生物学行为,如:细胞增殖、凋亡、分化、耐药和侵袭转移等[1-2]。本文就近年来miR-21在结直肠癌肿的研究进展进行综述。

1 miR-21的概述

miR-21含22个核苷酸,在种属间高度保守,定位于17q23.1染色体FRA17B 脆性区域,其可通过自身的启动区域完成转录。miR-21最早作为“oncomir”被发现,很多癌症对其具有“致癌基因成瘾性”。miR-21作为一种癌基因,参与了肿瘤细胞的增殖、转化和转移等多种生物学行为。无论在实体肿瘤,还是在非实体瘤中均发现miR-21高表达。miR-21目前可被用来作为一种肿瘤标志物判断肿瘤分期、疗效和预后的指标。

2 miR-21调节食管癌的生物学特性

食管癌的发生发展是一个多基因、多因素和多阶段参与发生的过程。miRNA参与了食管癌发生发展等病理过程。其中以miR-21的研究较为深入。在食管癌组织标本中,miR-21过度表达。miR-21过表达与肿瘤情况、淋巴结转移及临床分期等相关[1]。研究表明以食管癌细胞为研究对象,当miR-21过表达时,不仅抑制了食管癌细胞的凋亡,而且促进食管癌细胞的增殖和转移[2]。敲除miR-21,降低食管癌细胞增殖、侵袭和迁移能力[1]。

miR-21通过多种途径促进食管癌的发生和发展。miR-21的作用靶点主要有第10号染色体同源丢失性磷酸酶张力蛋白基因(PTEN)、程序性细胞死亡因子4(PDCD4)等。Wu等[3]研究显示miR-21、PI3K、Akt在食管癌组织中高表达,PTEN在食管癌中低表达。食管癌中分化差伴淋巴结转移,PETN阳性率明显降低。通过抑制miR-21表达,PTEN表达明显上升,但PI3K和Akt明显下调,降低了食管癌细胞增殖、迁移和侵袭能力。表明在食管癌中,miR-21通过PTEN/PI3K/Akt信号通路促进细胞增殖、迁移和抗凋亡。Liu等[4]通过Shrna-erk1/2可以显著减低miR-21的表达水平,而ERK1、2过表达可以上调miR-21的表达。表明miR-21还可通过激活EPK1/2/MAPK通路促进食管癌细胞增殖、迁移和抑制细胞凋亡。研究[5]还表明,FASL、TIMP3和RECK是miR-21直接的靶向基因。

miR-21负性调控PDCD4的表达[6]。外泌体穿梭miR-21可使受体细胞miR-21过表达,通过作用于PDCD4和激活其下游的c-Jun氨基末端激酶(JNK)信号通路,促进细胞的迁移和浸润[7]。miR-21还可通过作用于K-ras基因,参与了食管癌的发展和转移[8]。另外,miR-21参与了miR-203抑制食管癌生长、侵袭过程[9]。

此外,miR-21可能有助于肿瘤微环境中的细胞串话(cross-talk)。Nouraee 等[10]将食管癌细胞与正常成纤维细胞共培养时,食管鳞癌细胞的miR-21表达提高,增加了细胞迁移和侵润能力。表明miR-21可能是一个重要的因素“激活”成纤维细胞转化为癌症相关成纤维细胞(CAF)。这些研究结果为CAFs和肿瘤微环境中肿瘤细胞形成与维持的胞外基质的作用提供了新的见解。

miR-21还参与了一些致癌因素如吸烟、缺锌和饮酒等诱发食管癌发生的过程。miR-21表达失调和食管癌发展与缺锌的程度相关[11]。缺锌时,miR-21过表达,而PDCD4下调,促进食管癌的发生[12]。大量饮酒可引起miR-21表达显著上升[13]。在食管鳞状细胞癌细胞株EC9706中,尼古丁可诱导miR-21表达上调,促进TGF-β依赖的上皮-间质转化(EMT)[14]。

3 miR-21在食管癌诊断中的作用

与癌旁组织相比,miR-21在食管鳞癌中过表达。miR-21主要分布在食管癌细胞相邻的基质细胞的细胞质中[9]。研究表明,miR-21在食管癌中表达上调,与食管癌的分化程度相关[15]。因此,miR-21可作为食管癌诊断的生物标志物[16]。

miR-21用于食管癌诊断的检测物有唾液、血浆、血清和癌组织。由于唾液、血浆和血清miRNA具有取材方便和损伤小,可通过相对无创的方式获取检;检测快速便捷等优点。这些特性使血清、血浆和唾液miRNA更适合成为肿瘤的诊断、疗效和预后评估的生物标志物。miR-21在食管癌患者血清中高表达。食管癌合并转移患者的血清miR-21浓度是正常组织的8.4倍。因此,血清miR-21可作为一种新的诊断和预后评估的肿瘤标志物[17]。Xie等[18]研究表明 唾液miR-21在食管癌患者诊断中的敏感度是89.7%,特异度为47.4%。叶敏华等[19]研究显示唾液和血浆miR-21在食管癌患者中显著高于对照组。Ⅰ、Ⅱ、Ⅰ+Ⅱ期食管癌血浆miR-21的诊断灵敏度分别为96%、64%和97%,特异度分别为44%,84%和56%;而唾液miR-21的敏感度分别为为90%,88%和89%,具有相同的特异度64%。无论食管癌分期,血浆miR-21表达均与唾液中显著正相关,诊断价值相当。因此,唾液miR-21的检测有望代替血浆检测。

4 miR-21在食管癌预后中的作用

miR-21可用于预测食管癌患者预后[20-22]。miR-21高水平表达组,食管癌总体生存率(OS)越差[23]。miR-21单独或与炎症基因CRY61、CTGF和IL-18联用,可预测食管预后,这有助于临床治疗决策的选择[24]。术后患者血浆miR-21高浓度组比低浓度组的术后病因特异生存率更低(3年生存率为53.4%、81.5%)。多因素分析显示,高浓度血浆miR-21是一个独立的预后因素[25]。

在食管鳞癌患者中,通过Kaplan-Meier生存分析示血浆miR-21高表达的食管癌患者,无进展生存(PFS)和OS较对照组缩短。表明miR-21高表达,患者预后差[26]。包含25项研究2258例食管癌患者的meta分析中,miR-21高表达组比miR-21低表达组的预后更差,OS差[27]。而Winther等[28]研究表明miR-21是否可作为预后生物标志物与食管癌病理类型相关。在食管腺癌中,miR-21高表达,患者疾病特异生存越短。但在食管鳞癌中,miR-21并不能作为患者疾病特异存活的独立预后标志物。

miR-21可用于预测食管癌手术、化疗和放疗的治疗效果。与术前相比,食管癌患者术后血清miR-21水平明显降低。食管癌患者化疗有效时,miR-21水平明显降低,而化疗无效时,血清miR-21变化无统计学差异[29]。王光等[30]研究表明食管癌患者放疗后,完全缓解组、部分缓解组和无效组之间miR-21表达水平差异有统计学意义,miR-21的表达水平与放疗敏感性呈负相关。Kaplan-Meier分析显示miR-21高表达组的生存时间明显低于地表达组。因此,miR-21可用于预测食管癌放疗敏感性及预后。但Tanaka等[31]研究显示miR-21与食管癌辅助化疗敏感性及预后之间并无明显相关性。

5 miR-21可能成为食管癌治疗的新靶点

目前,食管癌仍以手术、放疗及化疗等综合治疗为主。即使经过综合治疗,食管癌患者5年生存率低,仅10%~30%。由于食管癌预后差,亟需寻找新的有效的治疗方案。miR-21 参与食管癌的发生和发展,因此,miR-21可成為食管癌治疗的潜在靶点[32]。食管癌患者的血浆外泌体可诱导食管癌细胞增殖。当外泌体提取后,食管癌患者血浆中并不能检测到miR-21。研究还表明外泌体miR-21表达与肿瘤分化程度,淋巴结转移和血行转移等相关。表明外泌体miR-21与肿瘤进展和侵润相关,可作为一个有效地癌症治疗靶点[33]。Huang等[34]研究显示抑制miR-21表达可显著增加食管癌细胞的放射敏感性和PTEN蛋白表达。此外,磷酸化Akt蛋白和PTEN下游分子表达也显著减少。因此,认为抑制miR-21,通过激活PTEN,提高放疗敏感性。在食管癌细胞,新的化疗药物Rawq01通过抑制miR-21上调PTEN的表达,从而抑制PI3K-AKT信号通路[35]。在食管鳞状细胞癌裸鼠移植瘤模型,miR-21可作为一种有效地治疗靶点。Liu 等[36]研究表明抑制miR-21可通过影响Ki-67、Caspase-3和Snail的表达可抑制移植瘤生长和转移。因此,提示miR-21可作为食管癌临床治疗候选靶基因。

6 小結

食管癌是一种常见的消化系统的恶性肿瘤,在我国发病率和死亡率高,严重威胁着人类健康[37]。随着对microRNA在食管癌中研究的深入,发现miR-21参与食管癌的发生发展,能调节食管癌的增殖、凋亡、侵袭和迁移等生物学特性。miR-21可用于食管癌的诊断和预后评估,并有可能成为食管癌治疗的新靶点。

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(收稿日期:2017-03-02 本文编辑:苏 畅)

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