ADAM9在实体肿瘤生物学中的相关研究进展
Research Progress of ADAM9 in the Biology of Solid Tumors

作者: 朱莉金 , 罗 琰 , 贾清玉 , 陈爱霞 , 赵园园 :青岛大学附属医院,山东 青岛;

关键词: ADAM9实体肿瘤研究进展ADAM9 Solid Tumors Research Progress

摘要:
去整合素–金属蛋白酶家族(adisintegrin and metalloproteinase, ADAMs)是一类锌依赖的跨膜糖蛋白,ADAMs家族分子具有相似的分子结构包括:结构域(单肽)末端金属域、整合素域、富含半胱氨酸的序列、膜近端上皮生长因子样序列。ADAM9在胶质瘤、黑色素瘤、前列腺癌、胰腺导管腺癌、胃癌、乳腺癌、肺癌和肝癌等实体肿瘤中均有过表达。免疫组织化学分析强调了ADAM9在实际癌细胞中的表达,并将其丰富的表达与临床病理特征联系起来,如总体生存期缩短、肿瘤分级较差、去分化、治疗耐药性和转移形成。本文综述了ADAM9在肿瘤中的研究现状,以及它在推动肿瘤进展方面的不同机制。

Abstract: A disintegrin and metalloproteinase family (ADAMs) is a zinc-dependent transmembrane glycoproteins. ADAMs family molecules have similar molecular structures including: a monopeptide terminal metal domain, an integrin domain, a cysteine-rich sequence, and a membrane proximal epithelial growth factor-like sequence. ADAM9 is over expressed in glioma, melanoma, prostate cancer, pancreatic ductal adenocarcinoma, gastric cancer, breast cancer, lung cancer, liver cancer and other solid tumors. Immunohistochemical analysis highlighted ADAM9 expression in actual cancer cells and correlated its rich expression with clinicopathological features, such as shortened overall survival, poor tumor grade, dedifferentiation, treatment resistance, and metastasis formation. In this paper, the current research status of ADAM9 in tumors and its different mechanisms in promoting tumor progression are reviewed.

1. 引言

金属蛋白酶蛋白家族(ADAMs ,a disintegrin and metalloproteinase)由33个成员组成,它们调控一系列细胞过程,包括细胞融合、细胞粘附和迁移 [1]。蛋白水解活性分子通过胞外区细胞因子、生长因子和受体的脱落来调控这些和其他细胞过程 [2]。约有一半的ADAMs具有蛋白水解能力,并被发现可以调节细胞膜细胞因子和生长因子、它们的受体和细胞粘附分子的活性,这对肿瘤发生的许多方面都有意义 [2]。在肿瘤组织和细胞系中都有许多蛋白水解物ADAMs的表达或上调的例子 [3]。

ADAM9作为ADAMs家族成员,参与肝癌、乳腺癌、肺癌、胃癌、肾癌、前列腺癌等多种恶性肿瘤发生发展、侵袭转移及预后 [4] [5] [6]。ADAM9对不同实体肿瘤的预后和诊断价值已被确定,基于它可能脱落一些能够刺激迁移、粘附和增殖的膜结合配体。已发现的ADAM9底物包括淀粉样前体蛋白(APP)、肝素结合表皮生长因子(HB-EGF)、胶原蛋白XVII、肿瘤坏死因子-p75、纤连蛋白、成纤维细胞生长因子受体2、胰岛素B链和明胶,这些在包括癌症在内的各种病理中都有涉及 [1] [7]。ADAM9在内皮细胞生物学中发挥着与其他ADAMs不同的重要作用,William R. English 等人发现ADAM9是内皮细胞–细胞连接的组成部分,并证明了它可以通过生态域相互作用进行自我关联;此外,虽然可溶性ADAM9外域发生在生理学上,但它调节内皮细胞间的相互作用而不是内皮细胞的通透性 [8]。

ADAM9在实体瘤中的过表达与侵袭性肿瘤表型和不良临床预后有关 [9] - [14]。例如,ADAM9 mRNA表达与胶质瘤的肿瘤分级和组织学类型有关,在低级别瘤变患者中,ADAM9的高表达与较差的临床结果之间存在显著的相关性,研究表明,ADAM9表达可作为低级别瘤变患者的预后指标,同时也是一个潜在的治疗靶点 [13]。Kim等发现ADAM9在胃癌的增殖和侵袭中起着重要作用,ADAM9可能是晚期胃癌的有效治疗靶点 [9]。ADAM9是miR-126-3p在达拉非尼耐药细胞中的一个靶点,它的沉默会损害细胞的增殖和侵袭性,并增加达拉菲尼的敏感性,ADAM9的沉默延迟了达拉菲尼抗药的建立 [15]。机制上,ADAM9可能通过非蛋白水解或蛋白水解机制驱动肿瘤进展。蛋白水解机制可能涉及细胞表面蛋白的脱落或加工,例如CDCP1或MHC I类多肽相关序列A (MICA),它们直接驱动肿瘤生长 [16]。另一方面,非蛋白水解机制包括肿瘤细胞与内皮细胞或瘤周基质细胞之间的相互作用,主要由不同的整合素家族成员介导 [17] [18] [19]。

2. 肝癌

有研究表明,ADAM9的过表达与肝细胞癌的临床病理特征相关,可能导致肿瘤发生发展、侵袭、转移及预后不良 [6] [16] [20]。Tao等人发现与ADAM9阴性患者相比,ADAM9阳性患者的肿瘤更大,分化更差,肝内转移、胆管和肝静脉侵犯更多,ADAM9在肝细胞癌组织中过表达,是肝切除术后总体生存的独立预后标志物 [6]。Arai等发现化疗药物索拉非尼(sorafenib)和雷格拉非尼(regorafenib)通过抑制分解素和金属蛋白酶9 (ADAM9),抑制肝癌细胞中MHC I类相关A链(MICA)的脱落 [21]。Sooyeon等使用癌症基因组图谱数据库,发现肿瘤组织中ADAM9的高表达与HCC患者较差的生存率相关(log-rank p = 0.00039),ADAM9 mRNA可能作为预测临床反应的生物标志物,而ADAM9-MICA-NKG2D系统可能是HCC免疫治疗的良好治疗靶点 [22]。Dong等研究发现ADAM9通过产生ROS介导肝癌细胞中IL-6诱导的上皮-间充质转化和转移,促进肝癌细胞的浸润和转移 [23]。Li等评估了ADAM9信号在四氯化碳致肝损伤反应中的重要性(CCl4)体内,他们的研究提示,ADAM9通过激活IL-6反式信号通路,调控肝细胞增殖、凋亡、血管生成和CYP2E1表达,在CCl4诱导的小鼠肝损伤中发挥重要的保护作用 [24]。

许多micro-RNAs已被证实为ADAM9调节因子和潜在的治疗靶点 [25] [26] [27]。Wan等报道HCC中miR-203的下调与患者生存期缩短相关,miR-203的上调降低了HCC癌细胞中ADAM9的表达,过表达miR-203可明显抑制细胞增殖、侵袭和诱导细胞凋亡 [25]。在HCC中,ADAM9作为miR-488的直接靶点,介导miR-488表达降低,从而诱导细胞增殖和侵袭 [26]。肿瘤抑制因子miR-126的缺失通过上调ADAM9促进了乙肝病毒相关肝癌转移的发生 [27]。

3. 前列腺癌

前列腺癌的临床研究表明,ADAM9的表达与疾病的预后相关。Fritzsche等人在198个样本的队列研究中发现与正常组织相比,肿瘤中ADAM9 mRNA和蛋白水平更高,并且与PSA无复发生存率密切相关 [28]。氧化应激诱导人前列腺癌细胞中ADAM9蛋白的表达,当人类前列腺癌细胞暴露于压力条件下(如细胞拥挤、缺氧和过氧化氢)时,ADAM9 mRNA和蛋白表达升高,ADAM9可能参与调控前列腺癌细胞的生存和进展,通过降低ADAM9的表达,可以观察到前列腺癌细胞的凋亡 [29]。

Josson等人证明ADAM9有助于前列腺癌的进展,可能是一个治疗靶点,作者发现ADAM9通过改变e-钙粘蛋白和整合素的表达,在前列腺癌进展和治疗耐药中起着关键作用 [30]。Liu等在体外和体内研究表明,ADAM9可能是治疗前列腺癌的药物靶点,在体外和体内的证据表明,通过慢病毒传递的小发夹RNA (shRNA)靶向治疗ADAM9基因表达,在小鼠前列腺癌骨转移模型中显著抑制了人前列腺癌细胞株的增殖,并阻断了肿瘤的生长,芯片数据显示,前列腺癌细胞中再生胰岛来源家族成员4 (REG4)表达水平明显下降,ADAM9基因表达下调 [31]。在前列腺癌组织和细胞系中,Hua等通过荧光素酶报告基因实验确定ADAM9为miR-126的靶基因,随后,他们使用Kaplan-Meier和log-rank分析来研究ADAM9表达与前列腺癌预后之间的关系,结果显示MicroRNA-126通过调控ADAM9抑制前列腺癌的增殖和转移 [32]。

4. 胃癌

许多研究也将ADAM9的表达与胃癌的不良预后联系起来。Carl-McGrath等在肿瘤组织和相应的非肿瘤组织以及5种胃癌细胞株中使用qPCR和免疫组化方法研究了不同类型ADAMs 9,12和15的发病机制 [33]。肿瘤组织中ADAM9表达明显高于正常胃组织,体外应用抗ADAM9抗体抑制胃癌细胞的生长,提示ADAM9通过信号分子的脱落或与粘附分子的相互作用在细胞增殖中发挥作用,在表达最高水平ADAM9的GC细胞中,敲除ADAM9减弱了细胞增殖,这与细胞周期阻滞在G0/G1期相一致 [33]。Wang等报道了ADAM9在胃癌组织中的异常表达与不同的临床病理特征如局部浸润、肿瘤大小、淋巴结转移、肿瘤–淋巴结转移相关 [34]。此外,他们发现在胃癌细胞中,ADAM9作为胃癌生长的启动子,在转录后受到miR-126的负性调控,这与在其他实体肿瘤中所做的研究相一致 [34] [35] [36]。Liu等通过靶向关联分析、双荧光素酶分析、qRT-PCR和western blot分析结果验证了miR-129-5p能够靶向ADAM9 mRNA的3'UTR并调控其蛋白表达,发现MiR-129-5p通过靶向ADAM9在胃癌进展中发挥抑癌作用 [37]。

Kim等人证明ADAM9在胃癌进展中起关键作用,这取决于其蛋白酶活性。使用RAV-18 (一种ADAM9阻断抗体)抑制ADAM9活性仅在高ADAM9表达的GC细胞中显示了酶活性的剂量依赖性下降;低氧条件下的免疫印迹分析表明,这些细胞系的侵袭性增加与ADAM9蛋白表达增加相关,提示缺氧和ADAM9表达之间存在联系 [9]。

5. 胰腺癌

基因表达谱显示ADAM9在胰腺导管腺癌(PDAC)中明显过表达。Grützmann等人通过免疫组织化学分析和多因素分析证实,ADAM9的表达将PDACs与其他实体胰腺肿瘤区分开来,细胞质中ADAM9过表达与分化差和生存期缩短有关,ADAM9过表达可能促进了PDACs的侵袭性 [38]。Yamada等人在11个癌细胞和11个正常胰腺上皮细胞的微解剖样本中定量表达了ADAM9,结果显示,癌细胞表达的ADAM9水平高于正常上皮细胞(p = 0.016) [39]。Xing等人的一项研究也得出了同样的结果,他们发现胰腺癌组织和细胞系中miR-217低表达和circ-ADAM9高表达,与临床晚期及淋巴结转移密切相关 [40]。

Xing等人进一步的机制研究表明circ-ADAM9通过直接抑制miR-217提高PRSS3表达水平,从而激活ERK/VEGF信号通路,进而减轻了miR-217对PRSS3的抑制作用,circ-ADAM9沉默或miR-217过表达明显延缓了肿瘤的生长,两者的联合对肿瘤的发生发展具有抑制作用 [40]。最近的研究强调了microRNAs (miRNAs)在包括肿瘤进展在内的各种肿瘤过程中的重要调节作用。Wu DM等初步筛选了与胰腺癌相关的候选miRNA和相关基因,用miR-126-3p转染PANC-1细胞或沉默PANC-1细胞的ADAM9基因,以检查它们在胰腺癌细胞中的调节作用,结果表明骨髓间充质干细胞来源的外泌体MicroRNA-126-3p通过负向调控ADAM9,抑制胰腺癌细胞的增殖、迁移和侵袭,促进细胞凋亡 [41]。Hamada等研究了micro-RNA在胰腺癌中的抑瘤作用及其潜在的分子机制,他们对PDAC组织中micro-RNA表达的综合分析显示,与正常胰腺组织相比,miR-126表达降低。Hamada等实验结果表明胰腺癌细胞中miR-126的重表达降低了ADAM9的蛋白表达水平,抑制了AsPC-1和Panc-1细胞的迁移、侵袭和上皮标志物E-cadherin的诱导减少,MiR-126通过调控ADAM9在胰腺癌细胞中发挥抑癌作用 [42]。

6. 肺癌

肺癌研究结果表明,ADAM9过表达在肺癌的进展和转移调节过程中起着重要作用。Zhang等使用免疫组织化学方法研究了ADAM9在人类切除的非小细胞肺癌中的异常表达,与正常肺组织相比,ADAM9在肿瘤中高表达,并且与ADAM9表达低水平的非小细胞肺癌(NSCLC)患者相比,ADAM9表达高水平的患者5年生存率明显缩短(分别为56.9和88.9%),多因素分析也显示,ADAM9过表达是缩短生存时间的独立因素 [43] [44]。在肺癌中ADAM9的表达受很多因素的调控,circ_0020123可以通过海绵miR-488-3p的释放来抑制ADAM9的表达,促进非小细胞肺癌的进展沉默circ_0020123可明显抑制A549细胞的生长、迁移和侵袭,抑制细胞凋亡 [45]。Wan J.等的研究结果显示环状RNA circ_0020123作为miR-488-3p调控ADAM9表达的ceRNA,促进非小细胞肺癌的进展 [46]。microRNA-590通过靶向ADAM9抑制非小细胞肺癌细胞的肿瘤发生和侵袭性 [47]。Chang GH等发现槲皮素通过抑制ADAM9表达途径进而抑制肺癌转移能力 [48]。Shintani等人早期的研究发现,在A549和EBC-1细胞中ADAM9过表达通过调节其他粘附分子和改变对生长因子的敏感性,增强了细胞粘附和非小细胞肺癌细胞的侵袭能力,从而促进了向脑的转移能力 [14]。

Chang等在A549细胞系(NSCLC细胞系)验证了上述过表达研究,在A549肿瘤细胞中,通过RNA沉默方法下调ADAM9表达可以显著抑制细胞在体外的增殖、迁移、侵袭和诱导细胞凋亡,并在肺转移实验小鼠模型中抑制体内肿瘤生长 [49]。Chang等还采用TUNEL法检测Lv/sh-ADAM9处理后对A549人肺腺癌细胞系凋亡的影响,结果显示Lv/sh-ADAM9处理显著增加细胞凋亡,显著增加caspase-3、8、9活性(P < 0.05) [50]。ADAM9介导的脑转移在很久以后才被详细描述,Shintani Y等的研究发现ADAM9过表达通过调节其他粘附分子和改变对生长因子的敏感性,增强了细胞粘附和非小细胞肺癌细胞的侵袭能力,从而促进了向脑的转移能力 [14]。Lin等证明ADAM9增强了组织纤溶酶原激活物(tPA)切割和刺激前迁移蛋白CDCP1促进肺转移的能力,此外,肺肿瘤脑转移瘤中ADAM9的水平相对高于在原发性肺肿瘤中观察到的水平,ADAM9通过基于纤溶酶原激活剂的途径促进肺癌向脑转移 [51]。对临床标本的分析显示,高水平的ADAM9与高水平的CDCP1有关,这导致了较差的临床预后和高死亡率风险 [51] [52]。Chiu等的研究结果进一步支持了这些结果,miR-218在正常肺组织中含量丰富,但在肺肿瘤中受到抑制,在ADAM9介导的CDCP1表达过程中受到调控,他们发现CDCP1表达和活性增强与miR-128表达降低相关 [52]。虽然这些作者证实了ADAM9高表达与脑转移相关,但其作用机制尚不清楚。后续研究表明,血管生成是脑转移的关键步骤 [53]。血管重构中ADAM9调控基因的微阵列分析显示,在ADAM9沉默细胞中,血管内皮生长因子A (VEGFA)、血管生成素-2 (ANGPT2)和组织纤溶酶原激活剂(PLAT)的表达水平被抑制,从而导致体内血管生成、血管重塑和肿瘤生长的减少 [53]。免疫组化分析显示,同时高表达ADAM9和VEGFA或ADAM9和ANGPT2与不良预后相关。总之,这些结果解释了ADAM9如何通过调节血管重塑和血管生成来促进肺癌进展 [53]。Kossmann等人也证明ADAM9在侵袭性肺腺癌中以血管生成依赖的机制驱动转移。在裸鼠体内静脉注射ADAM9 (shADAM9)稳定下调的A549细胞,显示肺内结节数量减少,提示外溢和转移能力降低 [4]。将这些细胞皮下注射到裸鼠体内,与对照组相比,实验组裸鼠的肿瘤更小,只有少量新血管。这些结果在体外也得到验证,与对照组相比,A549 shADAM9细胞上清处理后,人脐静脉内皮细胞(HUVEC)的血管形成明显减少 [4]。

7. 乳腺癌

乳腺癌是一种常见的实体肿瘤,多种报告表明ADAM9在疾病进展中起重要作用。O 'Shea等人进行了初步研究,研究了与正常乳腺组织相比,浸润性导管/小叶性乳腺癌中ADAM9的mRNA和蛋白表达水平,他们的结果显示,ADAM9 mRNA在乳腺癌中经常表达(72/110, 60%),与正常乳腺组织相比(6/25, 24%) [54]。研究表明,miR-154通过靶向ADAM9抑制乳腺癌细胞的增殖、迁移和侵袭,ADAM9被确定为miR-154在乳腺癌中的一个新的直接靶点 [55]。Micocci等使用MDAMB-231浸润性导管乳腺癌细胞证明,RNAi沉默ADAM9在体外抑制肿瘤侵袭,而不影响增殖和迁移,这支持了ADAM9可能在乳腺癌的侵袭和转移中发挥作用的假设 [5]。数年后,Micocci等人通过使用MDA-MB-231细胞进行跨上皮细胞迁移实验证明了这一观察结果。与对照组相比,这些癌症细胞中ADAM9的RNAi沉默强烈抑制了它们通过HUVEC (50%)、HMEC-1 (40%),和 HMVEC-Der-dLy cells (32%)的迁移 [17]。这些结果证实了ADAM9参与MDA-MB-231外渗,这一过程包括通过血管系统迁移、粘附内皮细胞、外渗并最终侵入继发组织 [17]。

Moelans等人对浸润性乳腺癌样本进行了分子谱分析,以确定驱动治疗进展和耐药性的基因。使用多路连接依赖探针扩增(MLPA),他们分析了104例患者样本中的20个乳腺肿瘤相关基因。在32%的样本中发现了ADAM9基因扩增,并与肿瘤有丝分裂指数、组织学分级和雌激素受体状态呈正相关 [56]。ADAM9-S以金属蛋白酶依赖的方式促进细胞迁移,而ADAM9-L以崩解蛋白域–整合蛋白结合的方式抑制癌细胞迁移,但独立于其蛋白水解活性 [57]。Jessica L Fry研究发现,ADAM9-S促进乳腺癌细胞迁移的方式需要其金属蛋白酶活性,而ADAM9-L抑制细胞迁移独立于其金属蛋白酶活性,ADAM9-L对迁移的抑制需要一个功能性的崩解素结构域和整合素结合 [57]。这种相反的表型可能与这两个变种的定位有关,因为ADAM9-S能够处理某些底物或细胞外基质,ADAM9-L由于膜系带而无法接触。表达分析显示,这两种ADAM9亚型均在乳腺癌细胞系和组织中表达,因此,ADAM9的膜系和分泌变异的相对水平是与乳腺癌进展相关的侵袭性迁移表型表现的关键决定因素 [56] [57]。这些结果得到了Mazzocca等人的证实,他们在基质检测中显示肝星状细胞分泌的ADAM9 (ADAM9-s)促进了不同人肿瘤细胞系的细胞侵袭 [58]。

三阴性乳腺癌(TNBC)是一种异质性疾病,由于缺乏有效的靶向治疗,预后较差 [59]。表皮生长因子受体(Epidermal growth factor receptor, EGFR)是一种在大多数三阴性乳腺癌(TNBCs)中经常过表达的靶向性受体(在一些研究中超过50%),EGFR的表达和激活在肿瘤等人的研究细胞存活、生长、侵袭和肿瘤转移中起重要作用 [60] [61] [62]。Wang等人的最新研究显示,组蛋白甲基转移酶NSD2通过刺激ADAM9-EGFR-AKT信号介导三阴性乳腺癌细胞的生存和侵袭 [63]。

8. 胶质瘤

越来越多的证据表明,ADAM9过表达在胶质瘤的进展中起着重要作用。癌症基因组图谱的表达预测(TCGA)强调,在多形性胶质母细胞瘤(GBM)中,ADAM9水平升高与生存期缩短相关。甘草查耳酮A (Licochalcone A, LicA)被报道具有抗肿瘤作用,Huang等人的研究观察到,LicA通过靶向MEK/ERK和ADAM9信号通路显著抑制了ADAM9的表达和人胶质瘤细胞(M059K, U-251 MG, GBM8901)的迁移侵袭活性,不表现出细胞毒性 [64]。高良姜(3,5,7-三羟黄酮)是一种天然的植物类黄酮,有研究发现高良姜可增加ERK1/2磷酸化,降低ADAM9表达,并防止A172胶质瘤细胞的侵袭 [65]。Fan等发现,与低级别胶质瘤(LGG)患者相比,在多形性胶质母细胞瘤(GBM)中ADAM9 mRNA表达水平更高 [13]。此外,在LGG患者中,侵袭性星形细胞癌ADAM9 mRNA表达水平较高,这与组织学类型、肿瘤分级、临床预后等相关 [13]。恶性胶质瘤的主要细胞外基质蛋白腱鞘蛋白c在体外被证实能刺激胶质瘤U87和U251细胞的侵袭 [66]。但其对脑肿瘤起始细胞(BTIC)发生胶质瘤的调控作用尚不清楚。通过一系列体外检测,包括微阵列分析和RNA干扰,Sarkar等人发现腱鞘蛋白c以金属蛋白酶依赖的方式促进了BTICs的侵袭,这种表型在蛋白酶抑制剂BB94的作用下被消除,基因表达的微阵列分析显示,ADAM9是这种侵袭性的潜在调节因子 [67]。

为了进一步支持这一观点,Liu等人发现ADAM9是miR-140在胶质瘤中的一个新的直接靶基因,他们的研究显示miR-140在胶质瘤组织和细胞系中下调,这与WHO对胶质瘤的分级相关。miR-140在胶质瘤细胞系中的表达恢复可通过直接靶向ADAM9减弱细胞的增殖、迁移和侵袭。此外,敲低ADAM9模拟了miR-140的抑癌功能,而过表达ADAM9则消除了miR-140在胶质瘤细胞中的抑制作用 [68]。Formolo等人利用蛋白质组学研究了四种胶质母细胞瘤细胞系(U87、U118、T98和LN18)的分泌体特征,证实了ADAM9在胶质瘤中的促肿瘤作用。这四种细胞系的侵袭能力有差异,其中U87侵袭性最强,这可能表明有额外的分泌蛋白促成了这种侵袭性表型。与侵袭性最小的GBM细胞相比,他们发现了几种U87细胞特异或高表达的蛋白,包括蛋白水解酶cathepsin B、ADAM9和ADAM10,这些蛋白已知可促进胶质瘤的侵袭 [69]。

9. 其它肿瘤

ADAM9过表达也与其它很多肿瘤的预后不良有关。Zigrino等对具有不同侵袭能力的黑素瘤细胞系的RNA分析显示,adam9在所有细胞系中均有不同数量的表达,与它们的侵袭和转移能力无关 [70]。Zigrino等的后续研究表明,ADAM9的表达在促进黑色素瘤细胞和瘤周基质成纤维细胞的相互作用中至关重要,这有助于黑素瘤侵袭 [18]。Seoparjoo等研究了ADAM9在子宫颈癌中的表达及其相关因素,在95例宫颈癌患者中,72例(75.8%)患者表现为ADAM9阳性表达,鳞状细胞癌是宫颈癌中最常见的类型(n = 67, 70.5%),与ADAM9阳性表达具有统计学意义的相关因素是肿瘤大小,远处转移及子宫颈癌的组织学类型(即鳞状细胞癌) [71]。在口腔鳞状细胞癌(OSCC)和口腔癌细胞系中,ADAM9表达增强,OSCC组织中ADAM9表达的免疫组化中位评分显著高于正常组织(P < 0.001)。此外,在OSCC中,高分化和中分化的OSCC中检测到强烈的ADAM9表达染色;ADAM9的表达也与细胞分化程度的增加相关(r = 0.557; P = 0.001) [72]。

Simona等研究发现,在黑色素瘤中上调miR-126-3p表达可以上调VEGF-A或ADAM9的表达,从而提高Dabrafenib药物敏感性 [15]。非瑟酮通过激活参与CTSS/ADAM9表达的MEK/ERK通路抑制了人类肾细胞癌细胞(RCC)的转移能力 [73]。MicroRNA-302a通过靶向ADAM9抑制骨肉瘤细胞的增殖、迁移和侵袭 [74]。

10. 展望

对于许多实体肿瘤,有多项研究将ADAM9与肿瘤进展、转移形成和/或恶化结果联系起来。ADAM-9是一种在实体肿瘤中表达强烈的锌依赖细胞表面蛋白酶,参与肝癌、乳腺癌、肺癌、胃癌、肾癌、前列腺癌等多种恶性肿瘤发生发展、侵袭转移及预后。深入研究阐述ADAM9在肿瘤中的表达与功能,并阐明其分子机制,有助于进一步认识恶性肿瘤的发生发展与转移的分子机制,拓宽临床治疗方面的应用前景,为肿瘤的早期预防、诊断提供新的潜在分子标志物,为靶向治疗肿瘤提供理论依据及新靶点。

NOTES

*通讯作者。

文章引用: 朱莉金 , 罗 琰 , 贾清玉 , 陈爱霞 , 赵园园 (2020) ADAM9在实体肿瘤生物学中的相关研究进展。 临床医学进展, 10, 2270-2280. doi: 10.12677/ACM.2020.1010343

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