修回日期: 2012-11-11
接受日期: 2012-11-15
在线出版日期: 2012-12-18
Metallopanstimulin-1(MPS-1)是核糖体蛋白S27E家族的一个成员, 其在除胎盘和脑以外的全身组织广泛表达, 但恶性增殖的组织和细胞中MPS-1的表达水平明显升高. MPS-1作为肿瘤标志物和肿瘤相关抗原在头颈部肿瘤和乳腺癌中被广泛研究. 在胃癌中研究结果显示MPS-1在胃癌组织中高表达, 其下调能够在体内和体外实验中抑制胃癌细胞的增殖和生长. 同时, MPS-1的下调能够通过抑制NF-κB信号通路进而促进胃癌细胞的自发性凋亡. 此外, MPS-1在结肠癌中也高表达且与肿瘤的恶性程度和预后密切相关. 因此, MPS-1可能成为肿瘤治疗的新靶点.
引文著录: 杨中印, 顾琴龙. 锌指蛋白Metallopanstimulin-1在肿瘤中的研究进展. 世界华人消化杂志 2012; 20(35): 3558-3563
Revised: November 11, 2012
Accepted: November 15, 2012
Published online: December 18, 2012
Metallopanstimulin-1 (MPS-1), belonging to the ribosomal protein S27E family, is ubiquitously expressed in all normal tissues except the brain and placenta. In addition, MPS-1 is highly expressed in malignant tumors and cells. MPS-1 as a tumor marker or tumor-associated antigen has been extensively studied in head and neck cancer and breast cancer. MPS-1 is highly expressed in gastric cancer. Knockdown of MPS-1 expression inhibits the growth of cancer cells both in vitro and in vivo and induces spontaneous apoptosis of gastric cancer cells by repressing the NF-κB signaling pathway. In addition, MPS-1 is also highly expressed in colonic cancer and has a close relationship with the degree of malignancy and prognosis. Therefore, MPS-1 may be a novel potential therapeutic target for cancers.
- Citation: Yang ZY, Gu QL. Advances in understanding the role of metallopanstimulin-1 in tumors. Shijie Huaren Xiaohua Zazhi 2012; 20(35): 3558-3563
- URL: https://www.wjgnet.com/1009-3079/full/v20/i35/3558.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v20.i35.3558
肿瘤的发生是一个多阶段、多因素参与的复杂过程, 其中涉及到一系列肿瘤相关基因的表达和结构异常, 肿瘤抗原就是这些异常基因的表达产物[1-3]. 肿瘤抗原能够被细胞和体液效应器识别的特性为恶性肿瘤的治疗开辟了一条新的途径, 许多的肿瘤抗原已经被鉴定并开展了相应的临床实验[4-8]. 肿瘤抗原筛选的方法有CTL克隆法和多肽洗脱法等, 但由于需要建立肿瘤特异性CTL克隆和操作技术难度大等局限性, 限制了其广泛应用[9,10]. 最近出现的重组cDNA表达文库血清学分析法(serological analysis of recombinant cDNA expression libraries, SEREX)利用肿瘤患者体内的体液免疫反应筛选肿瘤抗原, 避开了以往需要体外建立细胞株等实验难题, 可以应用于几乎所有类型的人类肿瘤相关抗原的鉴定[11-14]. 目前, 已有数千种肿瘤抗原基因通过SEREX方法被发现, 其中一些已被证实与肿瘤的发生、发展及肿瘤免疫具有一定的相关性[15-17]. MPS-1即是利用SEREX方法在多种肿瘤组织中筛选出的肿瘤相关抗原基因[18,19]. MPS-1是1993年Fernandez-Pol等[20]用TGF-βs和cAMP类似物刺激人乳腺癌MDA-MB-468细胞时发现的一个新基因. 目前, 关于MPS-1的研究主要集中在头颈部肿瘤、乳腺癌、前列腺癌[19,21,22]. 近期有报道MPS-1在胃癌细胞凋亡方面发挥了重要的作用, 下调MPS-1的表达能够抑制NF-κB的活性进而影响NF-κB下游的靶基因的表达而促进细胞的凋亡[23,24], 现就MPS-1在各领域的研究作一综述.
MPS-1编码的蛋白又名核糖体蛋白S27, 是一种多功能蛋白, 由84个氨基酸组成, 分子量为9.4 kDa, 属于核糖体蛋白S27E家族, 与鼠S27核糖体蛋白具有高度的同源性. MPS-1蛋白含有一个转录调控的DNA结合结构域, 分析发现他含有4个半胱氨酸残基以-Cys-X2-Cys-X15-Cys-X2-Cys-的形式排列, 从而形成一个锌指结构域, MPS-1蛋白可以通过这个结构域与含有cAMP反应元件(cAMP responsive element, CRE)的基因特异结合并调控他们的表达[25]. 此外, MPS-1还参与DNA损伤修复及异常改变mRNA的识别与结合[20]. 基因表达分析显示, MPS-1 mRNA在除脑和胎盘以外的正常组织中有着广泛的表达, 而在多种肿瘤如头颈部肿瘤、乳腺癌、前列腺癌及胃癌中高表达. 在增殖旺盛的细胞特别是起源于外胚层的细胞如黑色素瘤中MPS-1表达也明显增高[26,27].
针对MPS-1蛋白的免疫荧光、免疫组织化学结合Western blot等检测方法发现MPS-1蛋白在细胞浆和细胞核内都有表达, 且在不同的细胞中其定位并不一致[23,25]. 这可能是由于其在不同的细胞中的分布及所受刺激不同所致. 近来, 越来越多的报道显示核糖体蛋白除了作为细胞内蛋白质合成的场所外他还发挥了许多"核糖体外"的功能[28-30]. MPS-1所含的锌指结构域使其能够和特定的核酸结合从而调控他们的转录和翻译.
最近, He与Xiong等[31,32]发现MPS-1和他同一家族成员RPS27L都是转录因子p53的反应性靶蛋白. MPS-1和RPS27L的N末端都能与MDM2中间的酸性结构域结合. 因此, MPS-1或RPS27L与MDM2-p53形成三聚体的结构从而与p53竞争结合MDM2. 外源性表达的MPS-1能够抑制MDM2介导的p53泛素化降解[33-35], 并通过延长p53的半衰期, 使得p53表达水平升高.
Atsuta等[19]利用乳腺癌组织中抽提的mRNA构建了乳腺癌的cDNA表达文库, 并用SEREX方法筛选出肿瘤相关基因MPS-1, 并以此为基础进行研究. 免疫组织化学显示在所研究的125例乳腺癌患者组织中有50.4%的组织MPS-1呈阳性表达, Western blot显示在所有的乳腺癌细胞系中MPS-1高表达. 外周血淋巴细胞(peripheral blood lymphocyte, PBL)中MPS-1表达较低, 而在刀豆素(ConA)刺激下PBL中MPS-1的表达升高. Northern blot进一步证实MPS-1在增殖旺盛的组织、恶性组织和细胞中表达增加. 通过对大规模乳腺癌组织MPS-1蛋白表达水平的检测, 可以预见MPS-1能够作为一种肿瘤相关抗原, 并可能作为肿瘤疫苗用于肿瘤的免疫治疗.
Stack等[36]利用免疫组织化学方法对30例头颈部鳞状细胞癌(head and neck squamous cellcarcinoma, HNSCC)患者的癌组织中MPS-1的表达进行检测, 发现MPS-1在HNSCC中高表达, 并且运用放射免疫分析技术(radioimmunoassay, RIA), 蛋白芯片表面增强激光吸收/离子化飞行质谱(surface-enhanced laserdesorption/inionation-time of flight-mass spectra, SELDI-TOF-MS)等方法检测MPS-1在早期HNSCC患者中的表达, 并研究其是否能成为一个检测早期肿瘤的肿瘤标志物[21,37,38].
通过在可控条件下对血清进行热变性, 那些被MPS-1前体或载体蛋白激活和释放出来的MPS-1和MPS-1样蛋白统称为MPS-H, 通过RIA检测以确定MPS-1和MPS-1样蛋白的表达水平. Stack等[21]在实验中用RIA方法对125例HNSCC患者和25例正常不吸烟者、64例正常吸烟者为对照组的血清进行了MPS-H的检测, 发现HNSCC患者的MPS-H值为41.5 ng/mL, 而对照组分别为10.2 ng/mL和12.8 ng/mL, 患病组MPS-H水平明显高于对照组(P<0.001). 对于已经成功治愈的患者, 其第1年MPS-H水平明显低于临床确诊且未经治疗的患者. 此外, 很多的临床病例都证实成功治愈后HNSCC患者的MPS-H水平明显降低, 而对治疗无反应的患者血清内的MPS-H水平呈持续性升高.
正离子发射成像技术(fluorodeoxyglucose positron emission tomography, FDG-PET)的出现使得HNSCC的诊断和检测有了革命性的变化. 有报道称FDG-PET检测肿瘤的敏感性已达90%, 是检测肿瘤复发和转移的最准确的方法之一[39-41]. Scurry等[42]分别运用FDG-PET和RIA监测MPS-H的方法对HNSCC患者进行对比检查, 发现所检查的183例HNSCC患者中有103例2者的检查结果相符, 有12例MPS-H水平升高但是FDG-PET检查并没有发现肿瘤, 提示可能处于肿瘤早期的患者血液中MPS-H有变化但不能被影像检查出来, 另外48例患者的FDG-PET检查阳性而MPS-H并不升高, 提示可能是由于放化疗对肿瘤细胞的影响使其不能产生MPS-H, 也可能是PET的假阳性结果造成. 通过以上结果可以看出RIA方法检测MPS-H和FDG-PET之间有很好的符合度和精确性, 并且与PET相比MPS-H检测具有费用低、方便和快捷的优势. 所以, MPS-H检测有可能成为除FDG-PET之外的又一辅助诊断和检测手段. 该检测方法能否成为临床上的常用筛查手段还需要大规模的临床实验的进一步验证, 但其改进后的检测方法作为辅助的检测手段值得推荐.
SELDI-TOF-MS是新近兴起的蛋白质组学技术, 利用该技术可以准确的鉴定出患者血清样本中相关蛋白的表达图谱[43-45]. 通过运用该技术对HNSCC患者的血清进行检测, 质谱检测发现血清中有一10.68 kDa的峰值. 进一步用抗MPS-1 IgG做IMAC3蛋白芯片(SELDI免疫方法)[46,47]检测, 得到的同样的蛋白峰值而阴性对照则没有, 这些数据显示10.68 kDa这条蛋白质谱即为MPS-1蛋白[42].
SELDI-TOF-MS是从传统的肿瘤检测手段向现代检测技术转变的一个范例[45,48]. 该技术能够以半定量方式对肿瘤标志物进行检测, 更为有意义的是他利用蛋白的结构而不是个体蛋白的改变来区分HNSCC患者和正常人群. 由于具有非常高的特异性和敏感性, 而且其收集的数据易于整理和分析, 因此具有很好的临床应用前景.
Wang等[18]通过构建2个胃癌cDNA表达文库, 然后使用SEREX方法对文库进行筛选, 共得到阳性克隆18个, 经测序得到18个cDNA片断序列的信息, 经筛查这些片段序列共代表14个基因, 其中13个为已知基因1个为未知基因, 包括MPS-1、PHF10、ENO1、RHOA、SMARCA4等, 并选取了MPS-1做进一步的研究. 通过RT-PCR、Western blot和免疫组织化学检测发现MPS-1在胃癌组织和6株胃癌细胞中高表达. 然后, 对90例胃癌患者胃癌组织的mRNA表达水平与临床病理特征进行了统计分析, 发现mRNA表达水平与肿瘤患者的性别、年龄、肿瘤大小、分化程度无关, 但与肿瘤临床分期具有相关性(P<0.05), TNM分期为Ⅲ、Ⅳ期患者标本中MPS-1的表达明显高于Ⅰ、Ⅱ期的表达. 为了进一步研究MPS-1在胃癌的形成和进展中所起的作用, 通过运用siRNA干扰技术将胃癌细胞SGC-7901细胞中的MPS-1特异性下调, 胃癌细胞的增殖和克隆形成能力都受到明显的抑制. 通过流式细胞仪、荧光显微镜观察发现MPS-1下调的胃癌细胞自发性凋亡明显增加. 荧光显微镜下, 10%-15%的细胞出现了典型的凋亡形态, 主要表现为细胞核染色质的浓缩和核破裂. Western blot显示, 细胞饥饿刺激后MPS-1下调的胃癌细胞中的Caspase3蛋白活化. 裸鼠体内成瘤实验观察30 d发现MPS-1下调组胃癌细胞成瘤的体积明显减小, 通过TUNEL检测移植瘤切片发现其中胃癌细胞的凋亡也明显增加. 继而用凋亡诱导剂Etoposide处理MPS-1下调的胃癌细胞发现相对于对照组, MPS-1下调组胃癌细胞对凋亡诱导剂的敏感性明显升高, 基因表达谱分析提示MPS-1下调后凋亡相关基因发生了差异性表达, 且生物信息学分析发现NF-κB及其下游的靶基因Gadd45β在MPS-1下调引起的胃癌细胞凋亡中起了重要的作用[49-51]. MPS-1下调抑制了NF-κB的活性并对Gadd45β起到负调控的作用, 从而激活该通路下游JNK的磷酸化进而促进胃癌细胞的凋亡[24].
综上所述, MPS-1下调能够通过抑制NF-κB的活性进而促进胃癌细胞的凋亡并能在体内和体外抑制胃癌细胞的增殖和生长.
Ganger等[52]报道了一例17岁的男性患者, 因腹痛入院治疗, 肠镜检查结果为升结肠结肠高分化腺癌. 遂行右半结肠切除术, 术中发现由2枚淋巴结阳性. 术后化疗和放疗6 mo后复查发现肝脏出现多发性转移灶. 随后行肝动脉栓塞治疗后, 肝脏转移灶大小未见变化但是肿瘤癌胚抗原(carcino-embryonic antigen, CEA)明显降低, 结肠镜检查显示在吻合口旁未发现明显病灶, 取吻合口旁组织活检, 免疫组织化学染色显示腺体局部异型性和腺窝变形, 未见明显复发肿瘤, 但活检组织中MPS-1的表达较正常结肠黏膜组织明显增加. 该患者随后又进行了腹腔镜探查术, 发现有腹膜转移, 并于疾病诊断18 mo后去世. 因此, 我们推测该例结肠癌患者病情进展快速的原因与MPS-1的高表达有直接的关系. 同样, 在结肠癌的其中MPS-1家族的其他成员也发挥了非常重要的作用, Wong等[53]发现核糖体蛋白RPS27a在结直肠癌中高表达并可作为一个早期反应基因. 因此, MPS-1的表达与结肠癌的进展及恶性程度密切相关.
作为一种在胃癌中新发现的肿瘤相关基因, 结合其在其他肿瘤如乳腺癌、HNSCC等的形成中可能起到的重要作用和其作为肿瘤标志物的特性, MPS-1可能成为肿瘤治疗的一个新的靶点. 但是目前尚不清楚MPS-1通过哪些途径在肿瘤的发生发展中发挥作用, 其作用机制需要进一步的研究.
随着肿瘤相关抗原筛选方法的发展, 越来越多的肿瘤相关抗原被发现并证实与肿瘤的发生发展密切相关. 肿瘤抗原能够被细胞和体液效应器识别的特性为恶性肿瘤的治疗开辟了一条新的途径, 许多肿瘤抗原已经被鉴定并开展了相应的临床实验. MPS-1即是多种肿瘤组织中筛选出的肿瘤相关抗原基因.
张国梁, 主任医师, 天津市第一中心医院消化内科
肿瘤的病因及相关致病危险因素复杂多样, 肿瘤相关抗原MPS-1的识别为进一步研究肿瘤发生的机制提供了理论依据, 也为肿瘤的靶向治疗提供了一个潜在的靶点.
目前关于MPS-1的研究主要集中于头颈部肿瘤、乳腺癌和胃癌等, 尤其在胃癌中MPS-1下调能够通过抑制NF-κB的活性进而影响NF-κB下游靶基因的表达而促进胃癌细胞的凋亡, 进而影响胃癌的发生和发展.
本文对核糖体蛋白家族成员MPS-1与头颈部肿瘤、乳腺癌、前列腺癌、胃癌和结肠癌等肿瘤的相关性作了详细阐述.
本文较为系统的总结了MPS-1在不同肿瘤中的相关研究, 为研究肿瘤的发生机制提供了理论支持, 并为肿瘤的生物学的治疗提供了一个新的靶点.
本文立题较好, 引用文献较多, 对胃癌及其他肿瘤的研究有一定指导作用.
编辑:田滢 电编:闫晋利
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