修回日期: 2017-03-06
接受日期: 2017-03-20
在线出版日期: 2017-04-18
结肠癌转移相关基因1(metastasis-associated in colon cancer-1, MACC1)最早在结直肠癌中被鉴定. 此后发现其在多种肿瘤中表达异常升高, 且与肿瘤转移呈正相关, 与患者预后呈负相关, 具有明确的促肿瘤转移作用, 是一个潜在的抗肿瘤治疗靶点. 近年来对MACC1调控机制的研究日益深入, 其被发现在维持肿瘤相关信号的活性, 转录激活部分促癌基因, 调控上皮-间质转化, 促进肿瘤血管形成等方面具有重要作用. 而其自身的表达又受到非编码RNA、单核苷酸多态性的调控或影响. 一个以MACC1为中心的肿瘤生长转移调控网络正逐渐浮出水面. 本综述拟对上述研究进展做一综述.
核心提要: 探明肿瘤复发转移的分子机制是肿瘤靶向治疗策略建立和药物研发的基础. 近期研究发现MACC1基因在维持肿瘤相关细胞信号活性, 调控肿瘤细胞恶性行为等多个方面具有重要作用. 一个以MACC1为中心的肿瘤转移调控网络逐渐清晰起来.
引文著录: 樊建雨, 张昱, 郭强. 以MACC1为中心的肿瘤转移调控网络研究进展. 世界华人消化杂志 2017; 25(11): 989-995
Revised: March 6, 2017
Accepted: March 20, 2017
Published online: April 18, 2017
The MACC1 gene was firstly identified in colorectal cancer. Recently, abnormal upregulation of MACC1 has been detected in multiple tumors. The expression of MACC1 is shown to be positively associated with tumor metastasis, but negatively with prognosis of patients, and it represents a potential therapeutic target for anti-tumor strategies. MACC1 has increasingly emerged as a key regulator in metastatic processes, and it has been identified to be able to maintain multiple tumor-associated signaling pathways, transactivate oncogenic genes, and regulate epithelial-mesenchymal transition and tumor vascularization. On the other hand, MACC1 is regulated and influenced by non-coding RNAs and SNPs. The present review will summarize the recent progress in understanding the role of the MACC1 regulatory network in tumor metastasis.
- Citation: Fan JY, Zhang Y, Guo Q. MACC1 regulatory network in tumor metastasis. Shijie Huaren Xiaohua Zazhi 2017; 25(11): 989-995
- URL: https://www.wjgnet.com/1009-3079/full/v25/i11/989.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v25.i11.989
结肠癌转移相关基因1(metastasis-associated in colon cancer-1, MACC1)于2009年由Stein等[1]在结直肠癌中首次鉴定. 由于其具有促进结直肠癌侵袭转移的能力, 故命名为此. 此后, MACC1成为肿瘤研究的热点, 其作为促癌基因的角色在肺癌[2]、胃癌[3]、卵巢癌[4]、食管癌[5]等多种实体肿瘤中被证实. 目前认为, MACC1通过维持肿瘤相关信号途径的活性, 转录激活下游促癌基因, 参与调控上皮-间质转化(epithelial-mesenchymal transition, EMT)、肿瘤血管形成等肿瘤恶性行为. 而其表达水平则受非编码RNA、单核苷酸多态性的调控方式影响, 从而形成一个以MACC1为中心的调控网络. 本文将从上述方面对MACC1的在肿瘤发生转移中研究进展做一综述.
MACC1基因定位于人基因组7号染色体(7p21.1), 包含7个外显子和6个内含子. 其编码序列含有2559个核苷酸, 经翻译后形成含821个氨基酸的MACC1蛋白[1,6]. MACC1和早先发现的SH3BP4在核酸和蛋白水平上分别具有49.3%和43.7%的同源性, 因此也被称为SH3BP4L[1]. MACC1蛋白含有一个富含脯氨酸共有序列的SH3结构域, 可通过该结构域识别并结合其他含有SH3结构域的蛋白(R/KXXPXXP). 实际上, 许多酪氨酸激酶或蛋白酶底物均可通过SH3结构域参与细胞信号通路的转导和调控. 一些含有SH3结构域的蛋白则具有活化酪氨酸激酶, 或提高底物特异性的能力. 鉴于此, MACC1被认为可通过其SH3结构域在信号转导中行使重要作用. 除此之外, MACC1蛋白结构中还含有SH2结构域、Eps15同源结构域, 以及多个酪氨酸激酶的磷酸化位点[7]. 这些蛋白质结构上的特点均提示MACC1可能在细胞信号转导调控中具有重要作用.
MACC1最初在人类结肠癌组织中被鉴定, 进一步的对其他组织进行表达分析提供了一些MACC1相关生理功能的线索. Stein等[8]通过对几种数据的综合比较发现在不同的正常组织中MACC1基因的表达水平不同: 肠、胃、垂体, 肾, 气管的表达相对较高, 其次是胰腺, 乳腺, 骨髓, 卵巢, 肺, 心脏, 肝, 和B-淋巴母细胞. 从起源于内胚层的组织开始, 即肠和胃, MACC1具有较高的表达水平, 而起源于中胚层的组织(肾、心脏)或外胚层的垂体和乳腺则表达水平较低. 这提示MACC1可能在内胚层衍生器官的发育过程中发挥重要作用.
MACC1在多种肿瘤中已被证实参与相关信号通路的调控, 其异常高表达往往伴随着相关信号通路的激活进而导致肿瘤的发生和转移. HGF-MET信号是公认的促癌性信号通路, 在细胞生长、上皮间质转化、血管生成、细胞运动、侵袭和转移中起着重要的促进作用. Stein等[1]在最初对MACC1的功能进行研究时发现, MACC1的表达水平与HGF的受体MET的表达水平呈正相关, 提高或敲低MACC1的表达水平, 能够促进或抑制MET的表达. 在结直肠癌转移组织中, MACC1与MET在胞核中均呈高表达, 而原位肿瘤组织中的MACC1和MET则主要在胞浆中表达[1]. 进一步通过EMSA和ChIP实验发现, MACC1能结合在c-Met启动子区的Sp1结合位点, 启动MET的转录表达[9]. 故而认为, MACC1通过转录激活MET而促进HGF-MET信号的活性, 参与调控肿瘤生长、转移等行为. 此后的研究也相继在胃癌[10-12]、肝癌[13]、卵巢癌[14-16]中证实MACC1对HGF-MET信号通路的正性调控作用. 值得一提的是, 在乳腺癌中同样异常高表达的MACC1却不和c-MET的启动子相结合, 更不诱导c-MET的表达[17,18], 提示乳腺癌中的MACC1可能参与HGF/MET以外的其他肿瘤信号传导.
除去HGF-MET信号通路, 相关研究还发现MACC1可能参与调节其他促癌性信号通路. Zhen等[19]发现结直肠癌中的MACC1能够诱导GSK3β磷酸化, 促进β-catenin入核, 启动cyclin D1、c-Myc和MMP9等下游靶基因的转录. 在鼻咽癌中, MACC1与β-catenin、MET的表达水平, 以及AKT的磷酸化水平呈正相关. 敲低MACC1的表达使得β-catenin表达下调, AKT磷酸化水平下降, 同时鼻咽癌细胞的生长、浸润和转移也被抑制[20]. MACC1还参与调节Ras/ERK信号通路. Wang等[21]在胰腺癌中发现MACC1参与维持RAS/ERK信号通路的活性, 沉默MACC1能够降低RAS和P-ERK1/2表达, 同时还导致衔接蛋白Gab2下调, 而Gab2与RAS/ERK和PI3K/AKT信号活性的维持密切相关.
EMT是指上皮细胞通过特定程序转化为具有间质表型细胞的生物学过程, 使上皮细胞来源的恶性肿瘤细胞获得迁移和侵袭能力, 是肿瘤细胞侵袭转移能力的重要标志. 在EMT进程中上皮细胞标志物表达降低, 如E-cadherin的降低, 同时间质细胞标志物表达升高, 如属于钙结合蛋白S100家族的S100A4和基质金属蛋白酶(matrix metallopeptidase, MMP)的升高. 相关研究[22-24]证实在结直肠癌、胃癌、肝癌组织中, MACC1 mRNA水平同S100A4和MMP的mRNA水平呈正相关. 细胞学实验发现, 过表达MACC1能够抑制肿瘤细胞中上皮标志如E-cadherin的表达, 同时上调间质标志如vimentin等, 进而促进癌细胞EMT进程, 增强其侵袭和转移能力[25-27]. 进一步研究[28]提示MACC1参与了乙酰胆碱诱导的胃癌细胞EMT变化, 其表达水平能够随乙酰胆碱刺激而上调. MACC1上调后通过激活MET/AKT信号来引起EMT相关标志分子的表达变化[10].
肿瘤血管生成是肿瘤发生、进展转移进程中的重要步骤. 肿瘤细胞、肿瘤基质细胞分泌或释放的各种细胞因子共同构成肿瘤血管生成的调控网络. 肿瘤细胞是肿瘤血管生成的启动子, 他分泌的MMP等水解酶能降解细胞外基质, 促使储存于细胞外基质中的促血管因子如VEGF等释放诱导血管生成, 也可直接表达多种促血管因子促进血管生成. 研究发现, MACC1具有明确的促进肿瘤血管形成等能力. Sun等[29]通过对患者胃癌样本的检测及细胞学实验发现, MACC1过表达等够引起VEGF-C/VEGF-D的表达升高, 沉默MACC1能够抑制HGF-MET信号通路的活性, 从而降低VEGF-C/VEGF-D的表达, 减少新生血管和淋巴管的形成. 该研究组进一步构建MACC1过表达的胃癌细胞株建立小鼠移植瘤模型, 结果表明随着MACC1的表达升高, 肿瘤组织微血管密度也随之增加.
近年来提出的血管生成拟态(vasculogenic mimicry, VM)是一全新的肿瘤内血管生成模式, 其特点为肿瘤细胞通过自身变形和基质重塑产生血管样通道, 通道内无血管内皮细胞衬覆, 即不需要血管内皮细胞的参与[30]. VM与EMT以及转录因子TWIST的激活关系密切. 一项近期的研究发现, MACC1表达水平与胃癌组织中的VM密度呈正相关. 上调MACC1能够促进TWIST的表达, 并诱导VM. 在HGF的刺激下, 胞浆内的MACC1、TWIST1和TWIST2进入胞核, 提示MACC1对VM的影响可能是通过调控HGF-MET信号途径得以实现[31].
Stein等[1]在最初鉴定MACC1基因的研究中即发现, MACC1能够与MET启动子区的Sp1结合位点结合, 启动MET的转录并激活HGF-MET信号途径. 这是有关MACC1转录因子作用的最早报道. 近期, 他们又发现MACC1能够转录激活SPON2--一种细胞基质蛋白的编码基因. SPON2被发现在结直肠癌中的表达水平和MACC1呈正相关, 高表达SPON2的患者, 其无转移生存期较低表达患者平均少8 mo. 体内体外实验均证实SPON2具有显著地促进肿瘤侵袭转移的能力[32]. 我国学者也发现MACC1能够转录上调TWIST1/2, 进而促进胃癌中的血管生成拟态过程[31]. 此外, 基于转基因动物模型的研究[33]将过表达MACC1的转基因小鼠vil-MACC1与APCmin小鼠杂交获得子代的vil-MACC1/APCmin小鼠, 子代小鼠自发形成的肠道除肿瘤体积、数量以及细胞的侵袭表型均较母代显著增加, 更重要的是, 两种肿瘤干细胞标志--Nanog和Oct4的表达水平也明显上调. MACC1是否通过转录调控Nanog、Oct4抑或其他肿瘤干细胞标志, 参与肿瘤干细胞特性的维持, 相信这个问题不久后即能获得答案.
除去行使转录调控功能, MACC1自身表达也受到其他转录因子的调控. Juneja等[34]不久前鉴定MACC1的启动子核心区域位于-426-(-18) bp之间, 该区域包含了AP-1, Sp1和C/EBP等几个转录结合位点. 进一步运用点突变和RNAi技术证实AP-1, Sp1和C/EBP等均可转录调控MACC1的表达.
MiRNAs是一类细胞内源性的非编码微小RNA, 大约由21-25个核苷酸组成, 在人体组织中广泛表达. 作为机体内固有的一种表观遗传性调控机制, microRNA通过与编码基因3'UTR区的结合, 诱导靶基因mRNA的降解或者阻遏mRNA的翻译过程, 从而负性调节靶基因的表达, 参与多种细胞进程的调控[35-38]. 依据靶基因对肿瘤起促进或抑制作用, 可将调控其表达的miRNAs大致归为抑制或促进肿瘤两个方面[39,40]. 目前已经证实参与调控MACC1表达的miRNAs或与之相关的miRNAs包括miR-143、miR-218、miR-200a、miR-338-3p以及miR-433[41-45]. miR-143、miR-433、miR-218、miR-200a和miR-338-3p分别在结直肠癌、肝癌和胃癌中靶向抑制MACC1的表达, 诱导肿瘤细胞凋亡, 削弱其增殖、侵袭和EMT等恶性表型. 值得注意的是, miR-218在结直肠癌中的表达低下与其编码序列所在的SLIT2基因受启动子甲基化沉默有关[42]. miR-1虽然不直接阻遏MACC1的表达, 但可靶向抑制MET的表达水平[44]. 因此, 结直肠癌组织中miR-1的表达沉默和MACC1的高表达成为促进HGF-MET信号活性的重要因素. 事实上, 上述五种miRNA在相关肿瘤组织中的表达均与MACC1呈负相关, 即处于表达低下或沉默的状态, 亦从另一个方面体现了其抑癌性miRNA的特点. 最新一项研究[46]发现内源性的长链非编码RNA(long non-coding RNA, lncRNA)XIST能够竞争性地阻碍抑癌性miR-497与其靶基因MACC1的结合, 成为MACC1在胃癌中异常高表达的原因之一. 该研究首次提出了lncRNA对MACC1的调控作用, 也再次说明来自于非编码RNA的表观遗传学调控是MACC1行使促肿瘤相关作用的重要机制.
理论上, 具有转录因子特性的MACC1除了调控编码基因的表达, 也能够转录调控非编码基因如miRNA的表达. 但相关研究成果尚未有报道.
单核苷酸多态性(single nucleotide polymorphism, SNP)是指在基因组水平上由单个核苷酸的变异所引起的DNA序列多态性. 他是人类可遗传的变异中最常见的一种. SNP作为人类基因组计划走向应用的重要步骤, 为疾病高危群体的发现、疾病相关基因的鉴定、药物的设计和测试以及生物学的基础研究等提供了强有力的工具. 目前, 在人类MACC1基因中一些单核苷酸多态性位点相继被发现, 其中的16个单核苷酸位点位于编码区, 而这些单核苷酸多态性大多数发生在弱保守区域[3]. Lang等[47]研究发现MACC1基因rs1990172位点G/G和T/G基因型的结直肠癌患者总生存期显著缩短(HR = 1.38, P = 0.023), 在校正了年龄、UICC分期等可变因素后结果依然如此(HR = 1.49, P = 0.007). 同样, 具有rs1990172位点G/G和T/G基因型的乳腺癌患者无病生存期(HR = 2.26, P = 0.004)和总生存期(HR = 3.13, P = 0.001)均显著缩短, 病情进展和死亡的风险显著升高[48]. 此外, 存在rs1990172和rs975263位点SNP的肝癌患者, 其接受肝移植后出现肿瘤复发的危险性显著升高(HR = 2.27, P = 0.001; HR = 2.16, P = 0.001)[49]. 有上述研究结果提示, MACC1基因的SNP可作为预测病情进展和判断预后转归的标记发挥作用.
MACC1最初在结直肠癌中被鉴定具有促肿瘤生长和转移的能力, 随后这一结论在胃癌、肝癌、食管癌等消化系肿瘤, 以及非小细胞肺癌、乳腺癌、神经胶质瘤等消化道外肿瘤中陆续被证实. MACC1的表达水平与多种肿瘤的转移进展、生存时间呈负相关, 且有作为独立预测因子的潜力. 以MACC1为核心的肿瘤调控网络是目前相关研究的热点. 随着各项研究的展开, 目前认为MACC1通过转录调控维持HGF-MET、WNT/β-catenin等肿瘤相关信号途径的激活, 参与调控肿瘤生长、EMT、肿瘤血管生成等恶性行为, 促进肿瘤进展和转移. 而其在肿瘤中的异常表达则受非编码RNA、单核苷酸多态性等调控方式影响. 鉴于上述研究成果, MACC1有望成为抗肿瘤治疗的重要靶点. 尽管目前以RNA干扰为主的靶向MACC1治疗尚未取得进展, 但由于MACC1多样性的调控与被调控网络, 仍然能够通过间接方式降低MACC1的促癌作用. 例如靶向HGF-MET信号途径的生物性抗体和化学抑制剂已经陆续进入临床试验阶段[50,51]. 基于此, 未来对以MACC1为中心的肿瘤调控网络继续深入研究, 将不断为抗肿瘤治疗提供新思路, 具有重要临床意义.
近来基于分子机制研究成果而研发的肿瘤靶向药物陆续进入临床应用, 并获得良好的治疗效果. 结肠癌转移相关基因1(metastasis-associated in colon cancer-1, MACC1)自2009年首次在结直肠癌中被鉴定后, 其在多种肿瘤中的促生长转移作用相继被证实, 而其中的分子调控机制更成为研究热点. MACC1有望成为又一个临床肿瘤治疗的靶点.
目前的研究对MACC1调控肿瘤细胞增殖、侵袭、转移、耐药以及肿瘤血管形成等多种恶性行为的机制已有较深入了解. 新的观点提出MACC1具有转录因子作用参与促癌基因甚至某些促癌性miRNA的转录激活, 但仍缺乏足够的实验证据. 该问题值得深入地研究探讨.
Schmid等发现SPON2的表达受MACC1的转录调控. 在体内和体外实验中, SPON2都表现出明确地促肿瘤生长转移作用. 临床样本分析中, SPON2在结直肠癌中的异常高表达与患者的预后呈负相关. MACC1/SPON2组合除具有预后评价指标的作用之外, 还可能为未来的靶向治疗提供思路.
本文较详尽地归纳总结了近年来对MACC1促癌分子机制的研究成果, 并指出对于MACC1作为转录因子调控下游基因转录这一方向值得深入研究.
本文对近期MACC1调控肿瘤进展转移的分子机制的研究进展进行了阶段性地阐述和总结, 将一个以MACC1为中心构成的分子调控网络呈现于读者. 对未来MACC1的深入研究有一定指导意义.
转录因子是一群能与基因5'端上游特定序列专一性结合, 从而保证目的基因以特定的强度在特定的时间与空间表达的蛋白质分子.
刘树业, 主任技师, 天津市第三中心医院医学检验中心; 田华, 副研究员, 上海交通大学医学院附属仁济医院上海市肿瘤研究所
作者从MACC1调控肿瘤相关信号通路活化、调控上皮-间质转化和血管生成、调控靶基因转录以及MACC1的SNP等方面对MACC1的促肿瘤侵袭转移调控机制做了相对全面的综述. 文章思路清晰, 语言表达通顺, 逻辑性较强, 有助于读者更好地了解有关研究进展.
手稿来源: 自由投稿
学科分类: 胃肠病学和肝病学
手稿来源地: 云南省
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编辑:马亚娟 电编:李瑞芳
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