修回日期: 2012-05-06
接受日期: 2012-06-01
在线出版日期: 2012-07-18
细胞凋亡与抗细胞凋亡信号通路在胚胎及淋巴细胞发育、免疫系统调控、组织稳定及肿瘤发生中发挥着重要作用. 研究发现凋亡抑制蛋白(inhibitor of apoptosis proteins, IAPs)在多种恶性肿瘤组织中高表达, 并与肿瘤的发生、发展、放化疗抵抗性及预后密切相关, 使其成为肿瘤分子靶向治疗的研究热点. 近年来, 多种靶向IAPs药物正在进行临床试验评估, 并在试验中显示出较好的治疗前景. 同样, IAPs在食管癌发生发展中有着重要的地位, 使其成为食管癌分子靶向治疗潜在的靶点. 本文主要对IAPs在食管癌分子靶向治疗的研究进展进行综述.
引文著录: 唐鹏, 黄华. 凋亡抑制蛋白家族在食管癌分子靶向治疗中的研究进展. 世界华人消化杂志 2012; 20(20): 1843-1847
Revised: May 6, 2012
Accepted: June 1, 2012
Published online: July 18, 2012
The apoptosis and antiapoptotic signaling pathways play a critical role in the embryonic and lymphocyte development, immune system modulation, and tissue homeostasis, as well as carcinogenesis. As inhibitor of apoptosis proteins (IAPs) are highly expressed in several neoplasms and are closely related to carcinogenesis, cancer progression, radiochemotherapeutic resistance, and prognosis, therapies targeting IAPs have become a research hotspot for molecular targeted therapy of tumors. In recent years, many agents targeting IAPs which are being evaluated in clinical trials are showing promising prospect for neoplastic therapy. As such, the identification of key roles of IAPs in esophageal cancer has revealed their potential value as therapeutic targets. This report reviews the progress in understanding the role of IAPs in molecular targeted therapy of esophageal cancer.
- Citation: Tang P, Huang H. Progress in understanding the role of inhibitor of apoptosis proteins in molecular targeted therapy of esophageal cancer. Shijie Huaren Xiaohua Zazhi 2012; 20(20): 1843-1847
- URL: https://www.wjgnet.com/1009-3079/full/v20/i20/1843.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v20.i20.1843
食管癌是人类常见的恶性肿瘤之一, 统计显示2008年全球新增食管癌患者约482 300例, 死亡患者约406 800例, 其发病率在不同地区间具有显著的差异性[1]. 我国是食管癌的高发国家, 食管癌在我国常见恶性肿瘤中发病率居第6位, 死亡率居第4位[2]. 目前, 食管癌的治疗方法以外科手术治疗及辅助放化疗为主. 早期食管癌及时根治预后良好, 但是早期患者症状不典型, 首次就诊的患者以中晚期为主, 肿瘤对放化疗的抵抗使食管癌患者总体预后较差. 探索食管癌发生发展及放化疗抵抗的分子机制是目前食管癌的研究热点. 近年来, 研究发现凋亡抑制蛋白(inhibitor of apoptosis proteins, IAPs)与食管癌的发生、发展、预后及放化疗抵抗密切相关, 本文主要对IAP家族在食管癌分子靶向治疗的研究进展进行综述.
细胞凋亡是机体为维持自身稳定, 在基因的调控下, 细胞发生自主有序死亡的生物学现象[3,4]. 细胞凋亡和抗细胞凋亡的动态平衡是维系生物生长发育及组织稳定的必要条件, 细胞凋亡的失调与肿瘤的发生、发展密切相关[5]. 1993年, Crook等[6]在感染杆状病毒的昆虫细胞中发现第1个IAP, 到目前为止在人体内鉴定出8个IAP家族成员, 分别为NIAP、XIAP/MIHA、cIAP-1、cIAP-2、Survivin、Apollon/BRUCE、ILP-2和Livin/ML-IAP. 研究发现IAPs是一类高度保守的内源性抗凋亡基因家族表达产物, 广泛存在于许多生物体内, 参与调控细胞凋亡、细胞周期、有丝分裂及核因子kappa B(nuclear factor-kappa B, NF-κB)信号通路传导, 并与肿瘤的发生、发展、放化疗抵抗性及预后密切相关[7-9].
IAPs的分子结构特征是包含1-3个杆状病毒IAP重复序列(baculovirus IAP repeat, BIR)结构域. IAPs通过BIR结构域与细胞凋亡主要执行者caspase的BIM结构域结合, 抑制caspase的活性, 进而抑制细胞凋亡[10,11]. 在XIAP、cIAP-1、cIAP-2、ILP-2和Livin羧基端的RING结构具有E3泛素连接酶活性, 直接调控自身及IAPs结合的caspase泛素化[12]. Apollon的UBC结构域与RING结构域的功能相似. cIAP1和cIAP2的CARD结构域通过调节与其他蛋白质间的相互作用, 参与激活caspase蛋白质复合体的形成[12,13]. XIAP、cIAP-1、cIAP-2和ILP-2的UBA结构域与连接Lys63偶联的多聚泛素化相关[14].
NF-κB信号通路参与调控免疫反应、炎症、细胞增殖、细胞凋亡及肿瘤发生发展等多种生理病理进程[8]. 依据不同的激活方式, NF-κB信号通路分为经典途径和非经典途径, IAP家族在经典途径中发挥正向调节作用, 而在非典型途径中表现为负性调节作用[15]. Mahoney等[16]研究发现c-IAP1/2是调控肿瘤坏死因子α(tumor necrosis factor-α, TNF-α)诱导NF-κB活化的重要因素, c-IAP1/2缺失将增强TNF-α诱导的细胞凋亡. Lu等[17]研究发现BIR1与TAB1的相互作用对于XIAP诱导NF-κB信号通路激活有着重要的作用, 破坏BIR1二聚体将阻止XIAP诱导的NF-κB激活.
内源性IAPs拮抗剂对维持细胞凋亡平衡有着重要意义. 第二线粒体衍生的caspase激活剂(second mitochondrial-derived activator of caspases, Smac)是一种约25 kDa的线粒体蛋白, 以二聚体的形式存在于线粒体膜间隙, 在细胞凋亡信号通路激活后, 与细胞色素C共同被释放到细胞质, 经修饰成熟后与caspase竞争连接IAPs的BIR结构域, 解除IAPs对caspase的抑制作用, 促进细胞凋亡[18]. Smac氨基端的丙氨酸-缬氨酸-脯氨酸-异亮氨酸结构域是抑制IAPs的结构基础. Smac通过与XIAP、cIAP1、cIAP2、Survivin及Livin的相互作用参与调控细胞凋亡的平衡[19]. 2005年, Hariu等[20]研究发现Livin通过BIR结构与Smac蛋白结合, 增强RING结构域的E3泛素连接酶活性, 促进Smac经泛素-蛋白酶途径降解, 进而抑制细胞凋亡. 2010年, Flanagan等[21]研究发现XIAP并不能阻止线粒体释放细胞色素C, 而是通过选择性地减少Smac释放, 从而抑制细胞凋亡. 此外, 研究还发现Omi、eRF3、XAF1等内源性小分子IAP拮抗剂同样能够促进细胞凋亡[22-24].
近年来, 研究发现IAPs在人类多种恶性肿瘤中异常表达, 并与肿瘤的发生、发展、放化疗敏感性及预后等密切相关[8,12]. IAPs在食管癌的研究对于进一步探索食管癌的发病机制、评估患者的放化疗敏感性及预后有着深远的意义.
Survivin是IAP家族中的分子量最小的成员, 参与调控细胞周期、细胞凋亡、信号通路传导、新陈代谢及环境适应性等多种生物学进程[25]. Survivin在大部分恶性肿瘤组织中高表达, 而在成人正常分化组织中不表达或微量表达, 其高表达与肿瘤的放化疗敏感性及预后密切相关[26-28]. 在食管腺癌方面, 赵俊杰等[29]通过检测Survivin mRNA和GW112 mRNA在反流性食管炎、Barrett's食管及食管腺癌中的表达, 结果显示Survivin和GW112基因高表达抑制细胞凋亡, Survivin在Barrett's食管及食管腺癌发生的早期阶段发挥着重要作用. 在食管鳞癌方面, Takeno等[30]研究发现Survivin在细胞质的表达与食管鳞癌的分化、侵袭性及预后密切相关. 进一步检测Survivin、Survivin-2B、Survivin-deltaEx3 mRNA在食管鳞癌组织中的表达, 结果显示Survivin-2B的表达水平与食管癌组织分化程度相关. Zhu等[31]等研究发现Survivin的表达水平与食管鳞癌患者的生存时间密切相关. 在Survivin高表达的食管癌细胞中, 放疗引起的肿瘤细胞死亡数较少, 结果显示Survivin的表达可用于评估食管鳞癌患者的预后及放疗疗效. 此外, 外周血中Survivin的表达同样与食管癌患者的放化疗疗效及预后密切相关, Survivin高表达预示患者的放化疗疗效及预后较差[9,32].
IAP家族中的其他成员对食管癌的发生发展也发挥着重要的作用. 2004年, Nemoto等[33]研究显示NIAP、XIAP、c-IAP1、c-IAP2在食管癌组织中表达增强, 并与肿瘤分化程度密切相关, 其在低分化组的表达较高分化组显著增强. 2007年, Zhang等[34]通过免疫组织化学、RT-PCR和Western blot检测在食管鳞癌、正常食管及多种食管鳞癌细胞系中XIAP的表达, 结果显示XIAP在食管鳞癌组的表达较正常食管组明显增强, XIAP的表达与肿瘤的化疗敏感性相关. 2008年, Chen等[35]采用免疫组织化学、Western bloting和RT-PCR检测不同分期食管癌组织中Livin及VEGF的表达, 结果显示Livin与VEGF的表达随着肿瘤的进展而增加, Livin与VEGF的表达呈正相关.
总之, IAPs与食管癌的发生发展、放化疗疗效及预后密切相关, 并将成为评估食管癌患者预后及放化疗疗效潜在的预测因子.
近年来, 研究发现通过RNA干扰(RNA interference, RNAi)、小分子IAP拮抗剂、反义寡核苷酸等方法抑制IAPs在肿瘤细胞的表达, 能够有效地促进肿瘤细胞凋亡, 提高肿瘤细胞对放化疗的敏感性[36-38]. 随着研究的进展, AEG40826、YM155、AEG35156等靶向IAPs的药物相继进入Ⅰ/Ⅱ期临床试验, 并在试验中显示出较好的治疗前景. 靶向IAPs的分子生物治疗在食管癌的研究中也取得了较大的进展.
RNAi是将与靶基因同源互补的双链RNA引入细胞, 特异性地降解靶基因mRNA, 造成靶基因在转录后沉默的分子生物学技术[39]. RNAi现已广泛地应用于基因功能研究及基因治疗探索, 为靶向IAPs治疗食管癌的研究奠定了技术基础. 2007年, Zhang等[34]研究发现小分子干扰RNA能够有效地抑制食管癌细胞XIAP的表达, 诱导食管癌细胞凋亡. 进一步的研究发现, 联合靶向XIAP的小分子干扰RNA能够增强食管鳞癌细胞对紫杉醇、顺铂、依托泊苷、氟尿嘧啶的化疗敏感性. 2011年, 陈力[40]采用慢病毒载体构建短发夹RNA-Livin系统并转染至食管癌细胞Eca-109, 结果显示靶向Livin的RNAi联合顺铂上调Caspase-3、Caspase-9的表达, 抑制Eca-109细胞的增殖, 促进其凋亡.
近年来, AEG40826/HGS1029、Compound C、Compound8等Smac类似物在前期研究中表现出较好的抗肿瘤作用, 并相继进入Ⅰ期临床试验评估[18,41,42]. 在食管癌方面, Xu等[43]通过检测具有不同化疗疗效的食管鳞癌组织中Smac的表达, 发现在36.8%食管鳞癌组织中Smac的表达显著下降, 化疗敏感组与化疗抵抗组间Smac的表达具有显著差异性. 通过敲除Smac基因将抑制顺铂诱导的肿瘤细胞凋亡, Smac类似物LBW242则增强顺铂诱导的肿瘤细胞凋亡, 恢复肿瘤细胞的化疗敏感性. 因此, 联合Smac类似物的化疗方案将为化疗抵抗的食管癌患者带来新的希望.
反义寡核苷酸是通过人工合成特异互补的短链DNA, 大小约13-30个核苷酸, 根据碱基互补原则, 与目标mRNA结合后阻止目标基因的转录和翻译, 并通过激活体内的RNase或ribozyme酶导致目标mRNA降解, 进而抑制目标基因的表达[44,45]. 靶向IAPs的反义寡核苷酸在肿瘤的治疗研究中已经取得了突破性的进展. 2011年, Nakahara等[46]研究发现靶向Survivin的反义寡核苷酸YM155通过抑制Survivin的表达, 进而抑制非霍奇金淋巴瘤、乳腺癌、非小细胞肺癌等肿瘤细胞及异体移植肿瘤的生长, 提示YM155可能在肿瘤靶向治疗中具有广阔的应用前景. 在Ⅰ/Ⅱ期临床试验中, YM155对食管癌、非小细胞肺癌、黑色素瘤等肿瘤患者表现出较好的人体安全性及潜在的临床应用价值[47-49]. 2011年, Holt等[50]研究发现, 靶向XIAP的反义寡核苷酸AEG35156能够有效地降低骨肉瘤、横纹肌肉瘤及尤文氏肉瘤肿瘤细胞中XIAP的表达, 促进肿瘤细胞凋亡, 增强骨肉瘤细胞791T对阿霉素、依托泊苷及长春新碱的化疗敏感性. 目前, AEG35156正在进行Ⅰ/Ⅱ期临床试验评估, 在早期试验中并未发现严重的不良反应, 其肿瘤治疗疗效仍有待进一步评估[18,51].
免疫逃逸是肿瘤细胞存活及转移的重要因素之一. 靶向肿瘤相关性抗原的肿瘤疫苗通过激活患者自身免疫系统, 诱导特异性的免疫反应, 进而清除肿瘤细胞, 是一种较理想的肿瘤治疗策略. Survivin在多种肿瘤组织中的高表达, 使靶向Survivin的肿瘤免疫治疗成为了近年来的研究热点. 2009年, Honma等[52]采用Survivin-2B80-88多肽疫苗治疗晚期及复发性泌尿道上皮肿瘤患者, 在Ⅰ期临床试验中未发现严重的不良反应. 在部分患者体内发现Survivin-2B80-88多肽疫苗诱导的特异性细胞毒性T淋巴细胞数明显增多, 并有部分患者的肿瘤体积缩小, 显示出较好的人体安全性及免疫效应. Survivin-2B80-88多肽疫苗在对晚期及复发性口腔肿瘤的Ⅰ期临床试验中同样显示出较好的人体安全性及潜在的治疗价值[53]. 目前, 虽然未见靶向Survivin的肿瘤疫苗在食管癌治疗研究的相关报道, 但我们相信随着研究的进展, 联合靶向Survivin的免疫治疗将为食管癌患者提供新的治疗途径.
IAPs与食管癌的发生、发展、预后及放化疗敏感性密切相关, 并可能成为食管癌较理想的治疗靶点. 随着研究的进展, 靶向IAPs的肿瘤治疗已显示出较好的治疗前景, 为食管癌的分子靶向治疗提供了潜在的治疗途径. 但是食管癌的发病机制是一个复杂的多基因和多步骤过程, IAPs抑制细胞凋亡及肿瘤放化疗抵抗的分子机制仍不完全清楚, 靶向IAPs肿瘤治疗的疗效及潜在的不良反应仍有待进一步的临床试验评估. 我们相信随着分子生物学技术的发展及靶向IAPs肿瘤治疗的研究进展, 联合靶向IAPs的分子生物治疗将使更多的食管癌患者从中受益.
食管癌的放化疗抵抗性是目前食管癌治疗的难题. 凋亡抑制蛋白(IAPs)在多种恶性肿瘤组织中高表达, 并与肿瘤的发生发展、预后及放化疗抵抗性等密切相关. 探索IAPs在食管癌发生发展及放化疗抵抗性的作用机制对食管癌的分子靶向治疗有着深远的意义.
杜祥, 教授, 主任医师, 上海复旦大学附属肿瘤医院; 李增山, 副教授, 中国人民解放军第四军医大学病理教研室
近年来的研究发现IAPs与恶性肿瘤的发生、发展、预后及放化疗敏感性密切相关, 使其成为了肿瘤分子靶向治疗的研究热点. 但是IAPs抑制细胞凋亡及肿瘤放化疗抵抗的分子机制仍未完全清楚, 靶向IAPs治疗潜在的不良反应及疗效仍有待进一步评估.
本文系统地介绍了IAPs的结构、功能及信号传导通路, 重点阐述了IAPs在食管癌发生发展及放化疗抵抗性的作用和靶向IAPs在食管癌治疗的研究进展.
本综述较为系统地介绍了细胞凋亡相关信号通路在肿瘤, 尤其是在食管癌发生和发展中的作用和应用前景, 对于提示该类分子作为食管癌诊断标志物及治疗靶点具有潜在意义, 且文献复习较为全面, 具有较好的理论和实践指导意义.
编辑:张姗姗 电编:闫晋利
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