miR-22在胃癌中表达与临床病理意义
The Expression and Clinicopathologic Significance of Mir-22 in Gastric Cancer

作者: 唐 仪 :南华大学附属湘潭医院病理科,湖南 湘潭; 唐云云 :永州职业技术学院基础医学系,湖南 永州; 刘 芳 , 夏 红 , 曾 希 , 苏 琦 :南华大学肿瘤研究所,湖南省肿瘤细胞与分子病理学重点实验室,湖南省胃癌研究中心,湖南 衡阳; 苏 坚 :南华大学附属第二医院病理科,湖南 衡阳;

关键词: miR-22组织芯片原位杂交胃癌临床病理意义Mir-22 Tissue Microarray In Situ Hybridization Gastric Cancer Clinicopathologic Significance

摘要:
目的:探讨miR-22在人胃癌组织的表达及临床病理意义。方法:采用组织芯片与原位杂交技术检测89例胃癌组织及41例正常组织中miR-22的表达水平。结果:原位杂交结果显示,miR-22胃癌组织中的表达水平较正常胃粘膜组织明显下调(P < 0.01)。在89例胃癌组织中,miR-22的表达水平与患者的临床分期和淋巴结转移呈负相关(P < 0.01)。结论:miR-22在胃癌中表达下调,并与胃癌临床分期以及淋巴结转移相关。

Abstract: Objective: To investigate the expression and clinicopathologic significance of miR-22 in human gastric cancer. Methods: Tissue microarray and in situ hybridization were used to detect the ex-pression level of miR-22 in 89 gastric cancer tissues and 41 normal tissues. Results: In situ hy-bridization showed that the expression level of miR-22 in gastric cancer tissues was significantly down-regulated compared with normal gastric mucosa tissues (P < 0.01), and the expression level of miR-22 in gastric cancer tissues was positively correlated. In 89 cases of gastric cancer, the ex-pression level of miR-22 was negatively correlated with clinical staging and lymph node metastasis (P < 0.01). Conclusion: The expression of miR-22 in gastric cancer was down-regulated and correlated with clinical staging and lymph node metastasis of gastric cancer.

1. 引言

胃癌是最常见的恶性肿瘤之一,据2018年全世界185个国家统计的最新报告,每年新发胃癌病例约100万与死亡78.3万,发生率与死亡率分别居于第五位与第三位 [1]。我国是胃癌高发地区,每年约新发67.9万和死亡49.8万,发生率与死亡率仅次于肺癌而位于第二。由于患者就诊时大多已发生侵袭转移,常规手术和化疗效果较差,从而5年生存率低 [2]。因此,研究胃癌侵袭转移机制,寻找靶点具有重要的意义。

近年来,microRNAs (miRNAs)在肿瘤中的作用引起人们高度关注。miRNAs是一类含量丰富且高度保守的非编码内源性18~24 nt的小RNA分子,通过转录靶向性3′未翻译区下游基因的mRNA抑制mRNA的表达在肿瘤的发生和发展中起着决定性的作用 [3] [4] [5]。本研究采用组织芯片与原位杂交技术检测miR-22在人胃癌组织的表达及其临床病理意义。

2. 材料和方法

2.1. 组织标本

从南华大学附属湘潭医院收集胃癌89例与正常胃黏膜组织41例标本,病理诊断结果经两名以上病理学专家确诊,制成芯片。男性48例,女性41例,年龄28~76岁,平均年龄56.7岁。按WHO病理组织学分类,高分化与中分化腺癌21例,低分化腺癌68例。所有研究参与者均获得书面知情同意,并经华南大学伦理委员会批准,收集和使用组织的程序符合赫尔辛基宣言中制定的道德标准。

2.2. 主要试剂

原位杂交试剂盒购自武汉博士德公司;miR-22 mimics (5’-UAAUACUGCCUGGUAAUGAUGA-3’)由美国Exiqon公司合成;miR-22原位杂交探针序列(5’-ACAGTTCTTCAACTGGCAGCTT-3’)由美国Exiqon公司合成。

2.3. 原位杂交实验

烤片、二甲苯脱蜡、无水乙醇脱二甲苯、梯度酒精复水各5 min,无酶水洗1 min × 1次。3%过氧化氢灭活内源性酶,室温5~10 min,无酶水洗1 min × 3次。3%胃蛋白酶37℃消化15 min,PBS液洗5 min × 3次,无酶水洗1 min × 1次。后固定:1%多聚甲醛/0.1 M PBS固定10 min,无酶水洗1 min × 3次。预杂交:滴加预杂交液20 ul于切片上,置湿盒中, 55 ℃ 预杂交2 h。杂交:将miRNA探针按说明稀释于灭菌无酶水中,滴加杂交液20 ul于切片上,恒温箱中 55 ℃ 杂交过夜。次日用2 × SSC缓冲液漂洗5 min × 2次,0.5 × SSC缓冲液,0.2 × SSC缓冲液各漂洗15 mim × 1次。封闭:滴加封闭液, 37 ℃ 30 min,甩去残余液体,免洗。标记:滴加生物素化鼠抗地高辛,室温孵育2 h,PBST液洗5 min × 4次。滴加SABC液,孵育30 min,PBST液洗5 min × 3次。DAB显色,苏木素复染,水洗,中性树胶封片保存。评分标准:根据染色强度和阳性细胞分布比例进行综合评定,染色强度分为0~4分,0~1分为阴性,1~2分为弱阳性,2~3分为中度阳性,3~4分为强阳性;选取样本中三个具有代表性的高倍视野,进行分析细胞的分布比例。表达得分 = 强度 × 阳性细胞的比例,最大值为4,最小值为0。由两名病理学专家以双盲的方式进行评定,得分 > 或 = 2为高表达,<2为低表达。

2.4. 统计学处理

采用SPSS 16.0软件进行统计学分析。两组间比较用t检验,多组间比较用单因素方差分析,当P < 0.05时,为差异有统计学意义。

3. 结果

3.1. 原位杂交检测miR-22在胃癌的表达

采用组织芯片与原位杂交实验检测miR-22在89例胃癌和41例正常胃粘膜中的表达。图1显示,miR-22在胃癌中的表达较正常胃粘膜组织明显下调(P < 0.01)。根据染色评分标准,miR-22在正常组织36.59%低表达,63.41%高表达,而89例胃癌组织中有61.80%低表达,38.20%高表达(表1)。

Figure 1. The expression of miR-22 in gastric cancer detected by in situ hybridization

图1. 原位杂交检测miR-22在胃癌与正常组织的表达(×10)

Table 1. miR-22 is downregulated in gastric cancer

表1. miR-22在胃癌中低表达

3.2. miR-22在胃癌的表达与临床病理特征的关系

结果分析显示,miR-22在胃癌组织中的表达与患者年龄、性别、分化程度、肿瘤大小无统计学意义 (P > 0.05)。然而,miR-22的表达随着胃癌的临床分期增高而下调(P < 0.05),在有淋巴结转移的胃癌组织中miR-22的表达显著低于无淋巴结转移组(P < 0.01) (表2)。结果提示miR-22在胃癌的发生发展中发挥重要作用。

Table 2. The correlation between expression of miR -22 in gastric cancer and clinicopathological feature

表2. miR-22在胃癌中表达与临床病理学特征的关系

4. 讨论

研究表明,检测miRNA的方法包括实时RT-PCR、northern blot、微阵列杂交、克隆和测序以及原位杂交(In Situ Hybridization, ISH)等分子生物学方法,目前,ISH已被广泛应用于福尔马林固定石蜡包埋的肿瘤组织标本中miRNA的检测 [3] [4] [5] [6] [7]。ISH对三阴乳腺癌的分析显示,miR-150水平在淋巴结转移患者中显著降低,提示miR-150可能负性调控TNBC细胞转移 [3]。ISH检测miR-21在壶腹腺癌、壶腹发育不良病灶和正常十二指肠粘膜样本中的表达显示,所有正常的样本呈阴性或微弱miR-21表达,而80.8%的壶腹腺癌显示miR-21高表达 [8]。ISH检测显示,结直肠癌癌细胞和基质的成纤维细胞miR 221和miR 222水平升高,表明miR 221和miR 222在肿瘤间质中高表达与CRC患者的转移和恶性潜能有关 [9]。ISH分析表明,miR-4317在NSCLC组织中表达下调,尤其是在淋巴结转移和晚期临床分期组织中。并且,miR-4317高表达的NSCLC患者总体生存更好 [10]。采用ISH检测miR-182-5p在肝癌组织中的表达表明,miR-182-5p在肝癌高表达与肝癌术后预后不良及早期复发有关,结果RT-PCR检测相同 [11]。原位杂交显示,与正常细胞和组织相比,乳腺癌组织和细胞中miR-223表达明显降低,而STIM1表达明显升高,miR-223与STIM1表达呈负相关。MiR-223通过负性调控STIM1的表达,抑制乳腺癌细胞的增殖和侵袭,miR-223/STIM1轴可能是治疗乳腺癌患者的潜在治疗靶点 [12]。ISH显示miR-143在细胞质表达,主要在良性组织的腔细胞中表达,而miR-145表达在细胞核,在肌上皮细胞中有很强的染色。这两种miRNA都存在于乳腺癌上皮细胞和间质纤维母细胞中,表明miR-143和-145具有肿瘤抑制典型的功能特性和表达模式 [13]。ISH分析显示,胃肠的神经内分泌瘤(GI-NENs)的肝转移瘤中miR-96表达明显高于原发性NENs,与qRT-PCR检测结果一致,表明ISH分析可有助于评估GI-NENs患者 [14]。原位杂交显示,miR-21与MALAT1在原发性甲状腺髓样癌MTCs中表达增强。Real-time PCR检测原发性MTCs中miR-21和MALAT1的表达明显高于正常甲状腺,与ISH的结果一致,提示miR-21和MALAT1高表达可能调节MTCs进展 [15]。原位杂交显示,与非癌组织相比,胶质瘤癌组织的miRNA-375和CTGF表达有显著差异。miRNA-375高表达通过CTGF-EGFR通路抑制胶质瘤癌细胞的发生 [16]。原位杂交证实82例胰腺癌中miR-92b-3p表达水平明显低于非癌性胰腺组织。miR-92b-3p表达水平的降低与肿瘤大小、较高的淋巴结转移、晚期TNM分期和生存率降低密切相关。表明miR-92b-3p表达降低可能在PC的发生发展中发挥重要作用 [17]。原位杂交显示,在淋巴结阴性的侵袭性乳腺癌中,与良性乳腺组织相比,miRNA-494水平降低,并预示着乳腺癌死亡风险。因此,miRNA-494的检测可帮助淋巴结阴性乳腺癌患者识别侵袭性乳腺癌的亚群,miRNA-494可作为乳腺癌的预后判断标志,ISH方法可应用于常规病理诊断 [18]。miR-301a属于癌基因,ISH检测miR-301a在380例乳腺癌组织中的表达,发现141例miR-301a高表达,miR-301a的高表达与OS的降低有关,因此,在乳腺组织活检标本中检测miR-301a的表达,可能成为早期诊断的重要标志。并且,miR-301a可能作为乳腺癌患者的潜在治疗靶点 [19]。

原位杂交显示,miR-21在44%的胃癌组织与51%的肿瘤间质中高表达,肿瘤细胞的miR-21与临床病理因素无关,而间质miR-21与肿瘤分期、大小、淋巴结转移等因素有关,间质miR-21表达在肿瘤进展过程中逐渐升高,并且,在结缔组织增生性反应的浸润性区域表现出较强的间质阳性。qRT-PCR结果表明,肿瘤间质也比肿瘤和非肿瘤组织显示出更高的miR-21表达,提示间质miR-21表达与胃癌的进展密切相关,可能是胃癌治疗的靶点 [20]。本研究采用组织芯片与原位杂交检测表明,miR-22在胃癌组织中表达下调明显低于在正常组织,并且,miR-22低表达与临床分期和淋巴结转移密切相关。

大量研究证明,miR-22不仅在生物学上影响衰老的进程、能源供应、血管生成、EMT、增殖、迁移、侵袭、转移和细胞凋亡,而且,从遗传学或表观遗传学通过CNAs (拷贝数的改变)、SNPs (单核苷酸多态性)、甲基化、乙酰化与羟甲基化在不同的肿瘤中发挥抑制或促进肿瘤双重的效果。miR-22可能在某些肿瘤中成为一种有前途的、互补的甚至独立的肿瘤生物标志物,并对早期诊断、治疗、监督疗效和预后产生重要的作用 [21]。ATP citrate lyase (ACLY)是一种开始重新合成脂类的关键酶,在肿瘤细胞中表达上调,而miR-22在骨肉瘤、前列腺癌、子宫颈癌与肺癌中表达下调,ACLY与miR-22在肿瘤中表达呈负相关,miR-22通过靶向ACLY抑制肿瘤生存与转移,结果提示miR-22可转录后调控ACLY具有治疗骨肉瘤、前列腺癌、子宫颈癌与肺癌的作用 [22]。miR-22通过下调ACLY的表达抑制乳腺癌MCF-7细胞的生长和转移 [23]。miR-22在宫颈癌组织和细胞相对非肿瘤组织和正常人类宫颈癌HCK1T细胞表达下调。而组蛋白去乙酰化酶6 (HDAC6)在宫颈癌组织和癌细胞系中与miR-22呈负相关MiR-22通过抑制增殖和迁移,靶向HDAC6诱导宫颈癌细胞凋亡,发挥抑癌作用。这一新发现的E6/p53/miR-22/HDAC6调控网络可能是子宫颈癌的候选治疗靶点 [24]。miR-22在口腔鳞状细胞癌(OSCC)组织中的表达明显低于邻近非癌组织。miR-22高表达可显著降低OSCC细胞活力、迁移和侵袭。在OSCC组织和细胞中,miR-22表达与NLRP3表达呈负相关。miR-22可能通过靶向NLRP3在OSCC中发挥抑制作用 [25]。miR-22在膀胱癌组织中下调,miR-22高表达可体内外显著抑制膀胱癌细胞增殖、迁移和侵袭。并且,miR-22通过直接靶向MAPK1抑制细胞增殖/凋亡和通过抑制Snail和MAPK1/Slug/vimentin反馈环,在体外和体内抑制膀胱癌细胞EMT [26]。

目前,miR-22在胃癌中的准确表达、功能和机制尚不清楚 [27]。Jafarzadeh-Samani等显示,胃癌组织中miR-22的表达率较正常组织显著降低,表明miR-22可能是早期检测胃癌的良好诊断生物标志物 [28]。miR-22在胃贲门腺癌(GCA)组织较正常组织明显高表达,并且GCA患者血清miR-22水平明显较正常人增高,提示miR-22可能是胃癌诊断的生物标记 [29]。有人证明,胃癌患者血清中miR-22的水平较健康对照组显著降低,相反,miR-21的水平明显高于对照组。生物信息学分析显示,Sp1是miR-21靶点,而PTEN是miR-22的靶点,提示其是胃癌潜在的生物标志物 [30]。Zuo等发现,胃癌组织中miR-22的表达显著降低与患者整体生存率较差相关。miR-22作为抑癌基因,其高表达通过靶向MMP14和Snail明显抑制胃癌细胞的生长、迁移侵袭和EMT以及体内肿瘤生长、腹膜扩散和肺转移 [27]。幽门螺杆菌感染是慢性炎症导致胃癌发生的主要原因,而NLRP3在炎症发生过程中起着至关重要的作用。幽门螺杆菌感染可抑制miR-22的表达,促进NLRP3的表达,从而引发了上皮细胞失控的增殖和胃癌发生。然而,MiR-22可直接靶向NLRP3,在体内外降低其致癌作用。因此,miR-22抑制NLRP3并维持胃微环境稳态的机制,可作为胃癌干预的潜在靶点 [31]。

近年来,驱使miR-22高表达或研发上调miR-22的天然植物有效成分已成为治疗肿瘤新策略。miR-22在肾细胞癌中下调与肿瘤分期和淋巴结转移有关。实施miR-22高表达可抑制肾细胞癌细胞增殖、迁移侵袭与移植瘤生长和诱导凋亡。并且,miR-22高表达通过直接靶向SIRT1活化p53及其下游靶点p21与PUMA,裂解凋亡标志物CASP3与PARP和抑制EMT,表明miR-22高表达具有治疗肾细胞癌的新的潜在的作用 [32]。研究表明,miR-22在肿瘤发生发展中可调控抑制肿瘤干细胞CSC表型与功能。姜黄、大豆异黄酮、茶多酚、白藜芦醇、维生素D等天然植物有效因子通过靶向CSC相关基因上调miR-22抑制肿瘤增殖、迁移、侵袭与转移 [33]。黄酮类化合物白杨黄素chrysin具有抑制胃癌细胞增殖的作用,白杨黄素可改变miRNAs的表达,上调miR-22,可能是其作用的分子机制 [34]。进一步研究显示,用纳米包裹的chrysin与单体的chrysin相比,miR-22增加更为显著,表明纳米包裹的chrysin在抑制人胃细胞生长作用比单体的chrysin更有效 [35]。二烯丙基二硫(diallyl disulfide, DADS)是大蒜中烯丙基硫化物的一种脂溶性的有效成分,对多种肿瘤均有明显的抑制作用 [36]。我们发现,DADS可上调miR-22通过Wnt-1通路明显抑制胃癌细胞增殖与迁移侵袭 [37]。然而,DADS上调miR-22抑制胃癌细胞增殖与迁移侵袭的详细分子机制尚待深入研究。

基金项目

国家自然科学基金(81374013,31100935)。

文章引用: 唐 仪 , 唐云云 , 刘 芳 , 苏 坚 , 夏 红 , 曾 希 , 苏 琦 (2019) miR-22在胃癌中表达与临床病理意义。 世界肿瘤研究, 9, 61-68. doi: 10.12677/WJCR.2019.92009

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