MicroRNA-424在肿瘤发生中的作用和机制研究进展

刘萍，赵海苹，罗玉敏，*

(1.首都医科大学宣武医院神经内科，北京 100053； 2. 首都医科大学宣武医院脑血管病研究室，北京 100053)



MicroRNA-424在肿瘤发生中的作用和机制研究进展

刘萍1，赵海苹2，罗玉敏1，2*

(1.首都医科大学宣武医院神经内科，北京 100053； 2. 首都医科大学宣武医院脑血管病研究室，北京 100053)

MiR-424是miR-16家族成员。近年研究表明miR-424与肿瘤的发生、发展及治疗预后密切相关。本文对miR-424在乳腺癌、宫颈癌、肺癌、肝癌及结直肠癌等多种肿瘤及白血病中的表达变化、作用及机制进行综述。研究发现miR-424的表达受多种因素的影响，miR-424可作为肿瘤诊断、分期、预后的生物标记物，可用于明确肿瘤范围，也可作为肿瘤的治疗靶物。

miR-424；肿瘤；白血病

MiR-424是miR-16家族成员。MiR-16家族的种子序列为5’端种子区的第二个核苷酸开始出现AGCAGC (AGCx2)序列，该家族在细胞周期、增殖、凋亡及存活等过程中有重要作用。MiR-16家族主要包括miR-15a/b、miR-16、miR-195、miR-424和miR-497。其中miR-424的基因位于染色体Xq26.3上，在鼠类其同源物为miR-322。MiR-424可与miR-503聚集，从相同的初级转录物中转录[1]。成熟的miR-424也可与miR-450b形成簇[2]。研究表明，miR-424与肿瘤的发生发展及治疗预后密切相关，本文对miR-424在肿瘤中的表达变化、作用及机制进行综述。

研究发现miR-424在鳞状细胞癌、非小细胞肺癌、肾癌、胰腺癌中表达均上调；在宫颈癌、子宫内膜癌、卵巢癌、前列腺癌、结肠癌、肺癌中表达均下调[3-9]。Ratert等[10]发现在膀胱上皮癌中miR-424表达与正常组织相比差异无显著性。表明miR-424在不同种类癌症中的表达变化不同，可能是因为miR-424在不同组织和器官中的作用不同。

1 乳腺癌

临床研究显示，miR-424可作为乳腺癌诊断、预后的标记物。Dvinge等[11]发现约8%的激素受体阳性的乳腺癌中miR-424/503基因所在的染色体位置出现严重缺陷。Zhang等[12]分析微量人血清标本发现miR-424结合miR-199a、miR-29c可用于筛查出早期乳腺癌患者，敏感性为77%，特异性为92%，与乳腺钼靶照相技术相仿。Lerebours等[13]发现浸润性乳腺癌中miR-424表达升高，可见miR-424高表达与乳腺癌浸润性有关，预示不良预后。

MiR-424可促进乳腺癌细胞的增殖、转移和浸润。Cicatiello等[14]发现雌激素刺激乳腺癌细胞系 MCF-7时miR-424显著高表达，参与了雌二醇应答基因网络。Anne等[2]报道雌激素可上调MCF-7细胞中miR-424表达以促进增殖，该作用可被维甲酸抑制。Li等[15]也指出转移性高的乳腺癌中miR-424/503簇表达显著升高，过表达miR-424/miR-503可下调转化生长因子-β信号通路的抑制因子包括Smad7和Smad泛素化调节因子-2(Smurf2)的蛋白水平表达，并增强乳腺癌的转移能力；而下调乳腺癌细胞中miR-424/miR-503的表达时可抑制细胞转移，延长患者生存期。Pincini指出正常乳腺细胞MCF-10A细胞过表达信号分子(p130 Crk-associated substance, p130Cas)并活化原癌基因erbB-2后表现出浸润特性，同时MCF-10A细胞miR-424表达显著增高[16]。Drasin等[17]指出在转录因子TWIST1 或锌指转录因子SNAI1诱导的上皮间质转化中miR-424表达上调，可增加细胞活动性、减少粘连并诱导生长阻滞；乳腺癌原位肿瘤与正常乳腺组织比较miR-424表达增加，且miR-424表达与TWIST1/2和EMT相关基因呈正相关；转移肿瘤的miR-424表达比原位肿瘤低，可见miR-424在EMT-MET轴中有双向性，提示miR-424在肿瘤进展中可能具有双向作用：早期促进、晚期抑制。

2 宫颈癌、子宫内膜癌

临床研究显示，miR-424对宫颈癌的诊断和预后具有提示作用。与正常宫颈上皮组织比较，重度宫颈上皮内瘤变(cervical intraepithelial neoplasia，CIN)病灶组织的miR-424表达上调，结合其余11个miRs的变化可用于区分宫颈上皮内瘤变与正常上皮[18]。然而，Tian发现未明确意义的组织学异常上皮细胞中miR-424表达较正常宫颈细胞下降，并且，与HPV+的轻度CIN比较，HPV+的重度CIN组织中miR-424表达下降；与巴氏检测比较，miR-424结合miR-375与miR-218用于检测HPV+的2级以上宫颈上皮内瘤变具有更高的敏感性，且特异性相当[19]。与正常增殖宫颈内皮比较，高分化腺癌—宫颈微偏腺癌的miR-424-5p表达下降[20]。高危型人乳头瘤病毒阳性(HR-HPVs+)的宫颈癌组织与HR-HPV-的正常宫颈组织比较miR-424表达显著下降，提示miR-424可能作为宫颈癌的诊断和预后生物标记物[21, 22]。Xu等[23]也发现miR-424在宫颈癌组织中表达显著下降，并且miR-424的低表达与肿瘤低分化、高临床分期、淋巴结转移等提示不良预后的病理参数呈正相关。但Cheung等[18]比较宫颈癌病灶组织与正常宫颈上皮的miRs表达，未发现miR-424在二者间出现显著表达差异。推测与Cheung等仅用基因芯片检测且入选例数少有关。

miR-424可抑制宫颈癌、子宫内膜癌细胞的生长、转移和浸润。在宫颈癌细胞系SiHa及CaSki中miR-424过表达可促进凋亡、阻滞G1/S转化，抑制细胞生长、转移和浸润；miR-424直接靶向蛋白检查点激酶1(Chk1)的mRNA，下调Chk1和p-Chk1蛋白水平，下调基质金属蛋白酶MMP-9[21, 23]，提示miR-424可能成为宫颈癌的抗癌治疗靶点。Li等[7]发现子宫内膜癌组织及人子宫内膜癌细胞系Ishikawa和HEC-1B中miR-424表达均降低，而miR-424靶向抑制转录调节因子E2F7，可抑制子宫内膜癌细胞生长。

3 肺癌

研究显示，肺癌患者组织中miR-424的高表达提示其预后较差。Chen等[24]发现在肺癌细胞系及患者病灶组织中miR-424表达显著增加，并可能靶向THBS1 及 RGS5。Donnem等[25]发现非小细胞肺癌患者中，生存时间短的患者miR-424的表达明显高于生存时间长的患者，这可能与miR-424促血管生成有关。与此相似，接受化疗的晚期非鳞状非小细胞肺癌患者外周血中miR-424结合miR-29a、miR-542-5p、miR-502-3p、miR-376a和miR-500a可预测患者总生存期，miR-424高表达时总生存期缩短[26]。此外，Berghmans等[27]发现用顺铂和长春瑞滨治疗的非小细胞肺癌患者中支气管镜肺活检组织miR-424表达结合miR-200c、miR-29c和 miR-124组成参数公式，可用于预测患者预后好坏及肿瘤进展快慢。

4 肝癌

临床研究显示， miR-424在肝癌患者组织中表达降低提示其预后较差。Chiu等[28]指出1型糖原贮积病导致的肝细胞腺瘤患者与1型糖原贮积病无肝细胞腺瘤患者和其他原因导致的肝细胞腺瘤患者比较，前者肝细胞中miR-424表达下降，而原发性肝癌细胞系中miR-424表达显著下降。Yang等[29]发现miR-424在肝癌组织及细胞系中表达降低，并且miR-424的表达量与肝癌患者预后呈正相关。

基础研究表明，miR-424高表达可以抑制肝癌细胞增殖、迁移、浸润。MiR-424可使肝癌细胞SK-TRb阻滞细胞周期在G1期；体内及体外研究发现甲状腺激素可通过诱导miR-424/503前体转录，从而抑制表达核受体b(TRb)的肝癌细胞增殖、迁移及浸润[30]。Zhang等[31]发现失巢凋亡抵抗的肝癌细胞miR-424-5p表达显著降低，在肝癌细胞中过表达miR-424-5p直接靶向抑制β-连环蛋白/T细胞因子抑制子，维持细胞膜上E-cadherin/β-catenin复合物，可逆转失巢凋亡抵抗、阻止上皮间质转化、抑制迁移活性；裸鼠研究证实了上述结果；人体研究发现肝癌组织与正常肝组织比较miR-424-5p显著下调，miR-424-5p的表达与重度病理分级和TNM分级呈负相关，且血清中miR-424-5p表达趋势与组织中一致。Yu等[32]进一步明确miR-424表达在肝癌原位组织及细胞系中均下调，而过表达miR-424可靶向致癌基因c-Myb，抑制癌细胞增殖、转移和浸润。Yang等[29]发现miR-424可抑制Akt3/E2F3轴以抑制肝癌生长。Han等[33]指出肝癌肿瘤起始细胞中miR-424表达降低，miR-424等4个miRNAs可协同靶向维持TICs的关键因子B淋巴细胞白血病前体蛋白转录因子3和电压门控钙离子通道α2δ1。

5 胰腺癌

研究显示，miR-424在胰腺癌患者组织中表达升高，促进胰腺癌发展[34]。Wu等[35]发现miR-424-5p直接靶向细胞因子信号传导抑制蛋白6，活化ERK1/2信号通路，促进胰腺癌细胞增殖、迁移和浸润并抑制细胞凋亡，促进肿瘤发展。该发现有利于胰腺癌更好的诊断、预测预后及选择治疗方式。

6 结直肠癌

研究显示，miR-424在结直肠癌患者中的表达与在结直肠癌细胞系中的表达不同。Wang等[36]发现在无淋巴结转移的结肠癌患者中，癌变组织中的miR-424表达比癌旁组织明显上调。Guo等[37]证实在结直肠癌中miR-424表达上调。中国结直肠癌患者的miR-424表达比正常结直肠显著增高，但未发现miR-424与生存曲线存在相关性；体外研究发现结直肠癌细胞系HCT116和HT-29中的miR-424与正常结直肠黏膜比较表达下降[38]。Gaur等[39]发现miR-424在7种人结直肠癌细胞系中表达下降。出现这种体内体外相反结果，可能由于HCT116和HT-29细胞系来源于高加索人，即miR-424的表达可能与人种有关。Wang等[40]发现在手术冰冻组织和结肠镜活检组织中，在结肠癌中miR-424与miR-375表达均显著下调，而miR-92a表达显著上调，用miR-424结合miR-375、miR-92a制作评定模型(Logit模型)，用于区分结肠癌和腺瘤的准确率为94%，用于区分结肠癌与高分化上皮内肿瘤的准确率为89%。此外，通过对Ⅰ-Ⅳ期结肠癌患者miRs测定发现miR-424与肿瘤转移程度呈负相关[41]。

Guo等[37]指出miR-424对结直肠癌的作用不是通过靶向胰岛素样生长因子1受体。Wang[40]证实miR-424与其可能靶物—MAP2K1，MAPK3，SMAD3，WNT1，WNT7A 和MAP2K4的mRNA呈显著负相关。体外过表达miR-424时肿瘤细胞侵袭性降低[41]。在人直肠癌细胞系HCT116中miR-424可靶向Cdc25A，抑制细胞周期蛋白依赖性激酶2磷酸化，促进细胞周期G1期阻滞[42]。在人结肠癌、前列腺癌等肿瘤细胞中miR-424/503簇受抑制后介导Rictor上调，导致mTORC2复合物形成并使其活化，活化的mTORC2可活化AKT，以促进细胞增殖、转移和肿瘤生长及进展[43]。以上研究提示miR-424具有抑制结直肠癌的作用。

7 骨肉瘤

研究显示，miR-424表达在成骨肉瘤中上调，具有抑制骨肉瘤增殖、迁移、浸润的作用。Palmieri等[44]发现在多孔聚乙烯作用下人成骨肉瘤细胞系MG-63中miR-424表达上调。在人骨肉瘤细胞系U2OS中miR-424可靶向Cdc25A，抑制细胞周期蛋白依赖性激酶2(cdk2)磷酸化，促进细胞周期G1期阻滞[42]。Long等[45]证明miR-424作为肿瘤抑制物可靶向脂肪酸合成酶，下调其mRNA及蛋白水平，从而抑制骨肉瘤细胞系U2OS的迁移和浸润。

8 皮肤和头颈部鳞状细胞癌

研究显示，miR-424的表达在皮肤、舌、咽喉鳞状细胞癌中表达均上调[46,47]。Sand等[9]通过miRs微阵列分析发现皮肤鳞状细胞癌患者病灶处与病灶周边正常组织对比miR-424表达显著增加。Boldrup等[46]发现miR-424在舌鳞状细胞癌细胞中表达上调，而miR-424表达在病灶周围正常的舌组织中与完全正常舌组织比较表达下降，提示miR-424可能作为癌变范围的生物标记物，并对舌鳞状细胞癌的生长有作用。然而，Yata等[47]发现miR-424表达在头颈部鳞状细胞癌肿瘤干细胞表达低于普通肿瘤细胞。

9 其他肿瘤

在肾癌细胞系786-O中miR-424表达下调，靶向G2/M期检查点的关键激酶WEE1，进而使有丝分裂细胞周期依赖性蛋白激酶Cdc2活化，抑制增殖、取消G/M期阻滞以进入有丝分裂、促进凋亡[48]。在膀胱癌组织中miR-424表达降低，与膀胱癌恶性生长、高临床分级及不良预后相关，上调miR-424可通过靶向EGFR而抑制AKT信号通路从而抑制膀胱癌生长率及侵袭性[49]。并且DNA甲基转移酶DMNT1可抑制miR-424的转录[49]。在人前列腺癌细胞系DU145新建转移模型DU145-LN4中间质向上皮细胞转换机制之一为下调miR-424；过表达miR-424可出现上皮向间质细胞转化[50]。甲状腺乳头状癌中miR-424表达明显上调，并与肿瘤侵袭性相关[51]。

Zhang等[52]通过体内外试验对肿瘤相关成纤维细胞CAFs研究发现：CAF形成时miR-424表达升高，直接靶向氧化磷酸化向糖酵解转化的代谢开关—异柠檬酸脱氢酶3复合物的α亚基，减低α-酮戊二酸与琥珀酸和延胡索酸的比率，从而抑制脯氨酸羟化酶活性，使HIF-1α保持稳定，促进CAF的糖酵解抑制氧化磷酸化，促进肿瘤生长。

10 miR-424与抗肿瘤药物

除了对肿瘤细胞的作用外，miR-424还影响肿瘤对化疗药物的敏感性。Vilquin等[53]发现miR-424表达在稳定转染人芳香化酶基因的MCF-7aro(ER+乳腺癌细胞株) 中高于芳香酶抑制剂抵抗的细胞系包括Res-Let(来曲唑抵抗)、Res-Ana(阿那曲唑抵抗)；而在芳香酶抑制剂药物敏感的MCF-7aro细胞中抑制miR-424表达可显著降低细胞对来曲唑的敏感性；该作用可能与miR-424抑制PI3K/AKT/mTOR通路活化有关。癌干细胞中miR-424的高表达与卵巢癌化疗抵抗和肿瘤进展相关[54]。但是，Cecco等[55]指出，使用含未甲基化胞嘧啶-磷酸二酯键-鸟嘌呤基序的寡脱氧核糖核苷酸治疗人卵巢癌细胞系IGROV-1种植小鼠，与盐水治疗相比miR-424表达显著下降，但miR-424表达的下降对顺铂毒性未见显著促进作用。在肿瘤细胞(黑色素瘤细胞A375、胶质母细胞瘤细胞U251、结肠癌细胞HCT116)中低氧诱导pri-miR-424和成熟miR-424高表达，而过表达miR-424可降低肿瘤细胞对化疗药物阿霉素和依托泊甙的敏感性，抑制miR-424则出现相反作用；其机制为HIF1α与pri-miR-424启动子区上游的低氧反应域(HRE)结合，促进miR-424转录，并miR-424靶向PDCD4(肿瘤抑制物)，进而抑制凋亡、降低肿瘤对化疗的敏感性；裸鼠肿瘤异种种植模型也证实过表达miR-424可增加肿瘤对阿霉素的抵抗性；临床分析发现乳腺癌组织中miR-424与PDCD4呈负相关[56]。与此相反，Pouliot等[57]发现降低miR-424表达可介导肿瘤细胞出现顺铂抵抗，而过表达miR-424可通过靶向细胞周期激酶WEE1和CHK1促进顺铂抵抗的恶性肿瘤细胞凋亡。可见miR-424对不同的抗肿瘤药物作用机理不同，因而产生不同应答。

11 小结

总之，目前miR-424在肿瘤中的研究多集中在对miR-424表达变化方面，进一步的机制研究较少，缺乏全面的机制研究。MiR-424在不同肿瘤中表达可能相反，也有研究发现miR-424在同一种肿瘤发展的不同时期表达不同并且作用不同，在肿瘤早期可能促进肿瘤生长，而在肿瘤后期则表现为抑制作用[17]。以上研究指出miR-424的表达受多种因素的影响，其可作为肿瘤诊断、分期、预后的生物标记物，可用于明确肿瘤范围，也可作为肿瘤的治疗靶物，因此有必要进行更进一步的机制研究，以期应用于临床。

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Progress in research on the role of microRNA-424 in carcinogenesis and its related mechanism

LIU Ping1, ZHAO Hai-ping2, LUO Yu-min1，2*

(1.Department of Neurology, 2. Department of Cerebrovascular Diseases, Xuanwu Hospital,Capital Medical University, Beijing 100053, China)

A member of miR-16 family, miR-424 has been found to be closely related with tumorigenesis, tumor progrssion, prognosis and therapy. This article reviews the expression changes, roles and possible regulating mechanisms of miR-424 in leukemia and various tumors such as breast, cervical, lung, liver and colorectal cancers. Recent studies have demonstrated that the expression of miR-424 is affected by many factors, and miR-424 could be a biomarker of diagnosis, staging and prognosis in cancers,to identify the area of tumor, and be a target of therapy.

miR-424; Neoplasms; Leukemia

国家自然科学基金项目(81571280, 81201028,30770743)。

刘萍(1983-)，女，医师，博士，研究方向：脑血管病转化医学研究。E-mail: heliu1056@163.com

罗玉敏，教授，研究方向：脑血管病发病机制。E-mail: yumin111@ccmu.edu.cn

研究进展

Q95-33

A

1005-4847(2016)05-0529-06

10.3969.j.issn.1005-4847. 2016.05.017

2016-03-09