2015, Vol. 42文章信息
- 刘亚辉,缪景霞,李黎波,李爱民,罗荣城. 2015.
- LIU Yahui, MIAO Jingxia, LI Libo, Li Aimin, LUO Rongcheng. 2015.
- 高迁移率族蛋白B1在肿瘤发生发展中的作用
- Clinical Analysis of Multimodality Treatments for Pancreatic Cancer Patients with Liver Metastases
- 肿瘤防治研究, 2015, 42(07): 730-736
- Cancer Research on Prevention and Treatment, 2015, 42(07): 730-736
- http://www.zlfzyj.com/CN/10.3971/j.issn.1000-8578.2015.07.019
-
文章历史
- 收稿日期：2014-10-28
- 修回日期：2015-01-15
引用本文 |
2.510515广州,南方医科大学南方医院肿瘤科
2.Oncology Department,Nanfang Hospital,Southern Medical University,Guangzhou 510515,China
2011年,Hanahan和Weinberg更新他们的癌症中心理论[1],提出促进癌症发生的十大基本特性:支持增殖信号、回避生长抑制、逃避免疫损害、无限制生长、促肿瘤炎症、侵袭和转移、血管生成、基因不稳定和突变、抵抗细胞坏死、异常细胞代谢,而这些特征与高迁移率族蛋白B1(high mobility group box 1,HMGB1)的定位和过表达密切相关,所以把HMGB1放在现代理解癌症生物学的核心位置。HMGB1被强调在许多肿瘤中起关键作用[2],包括肾癌、肺癌、胰腺癌、胃癌、结直肠癌、肝癌、乳腺癌、前列腺癌、宫颈癌、血液系统肿瘤及黑色素瘤等。HMGB1在肿瘤中的"双刃剑"作用,目前认为最重要的原因是其在肿瘤细胞中的翻译后修饰,翻译后修饰决定HMGB1在细胞中的定位及功能[3]。
1 HMGB1的结构 1.1 一级结构HMGB1是由215个氨基酸残基组成的单链多肽,含两个DNA结合域:A-box (9~79氨基酸序列)、B-box (95~163氨基酸序列)及C-tail (186~215氨基酸序列),DNA结合域是维持DNA有效弯曲和折叠所必须的。在细胞中,C-tail的缺失使HMGB1与DNA及蛋白质结合疏松;缺少C-tail的HMGB1过表达阻止各种靶向基因的表达。细胞外的B-box引起炎性反应,而A-box具有抗炎活性,且与C-tail结合后能够增强A-box的抗炎活性[4]。细胞外HMGB1能结合一些蛋白,他们之间的相互作用对HMGB1的激活和功能起着重要作用:7~74氨基酸序列负责结合p53反式激活域引起相关基因转录;89~108氨基酸序列结合TLR4引起炎性反应;150~183氨基酸序列负责结合RAGE引起细胞迁移,见图 1。
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| TLR4:Toll-like receptor 4;RAGE:receptor for advanced glycation end products;ROS:reactive oxygen species;A:primary structure of HMGB1;B:the change of redox status and tertiary structure of HMGB1 along with the increase of ROS 图 1 高迁移率族蛋白B1的结构 Figure 1 Structure of high-mobility group box 1(HMGB1) protein |
HMGB1的二级结构主要与DNA的结合和改变DNA弯曲度及染色质重组有关[5]。
1.3 三级结构HMGB1结合域中的三个半胱氨酸(Cys23、Cys45、Cys106)与C-ail相互作用维系着HMGB1的三级结构,Cys106被丝氨酸替代后引起HMGB1由胞核进入胞质。Cys23与Cys45可通过氧化折叠过程形成分子内二硫键[6]。不同程度氧化的HMGB1分别与不同的受体和DNA结合,发挥迥然不同的作用,所以细胞氧化环境的改变可以改变HMGB1的氧化修饰从而影响HMGB1的结构、定位及功能[7]。
2 HMGB1翻译后修饰目前发现HMGB1的翻译后修饰有6种形式:乙酰化、腺苷二磷酸(ADP)-核糖基化、甲基化、磷酸化和氧化,这些修饰在HMGB1的定位及功能中起重要作用,其中决定其功能最主要的修饰为氧化修饰;糖基化,HMGB1糖基化数量极少,其功能不明确[8]。
2.1 乙酰化HMGB1可在赖氨酸2、11及81序列上(Lys2、Lys11、Lys81)上发生乙酰化,乙酰化的HMGB1与DNA结合力增加[9],与同源的DNA多聚酶α相互作用介导DNA的复制。在LPS、IFN、丁酸钠及低氧等多种刺激下,HMGB1发生乙酰化,随后进入胞质并通过出胞作用释放至胞外,乙酰化可限制HMGB1再返入胞核。
2.2 ADP-糖基化HMGB1的ADP-核糖基化在肿瘤细胞中增加,是细胞死亡尤其是细胞坏死中介导HMGB1核输出和释放的必须形式。在细胞胞外,ADP-核糖基化HMGB1结合PS和RAGE,抑制胞吞作用,进一步加强炎性反应[10];在细胞内,ADP-糖基化HMGB1的缺乏导致多聚酶1(poly ADP-ribose polymerase 1,PARP1)的过度激活和损伤,进一步导致肝细胞死亡,这些发现提示在调节细胞死亡上面PARP1与HMGB1的ADP-核糖基化有交互作用[11]。
2.3 甲基化在透明肾细胞癌[1 2]、中性粒细胞[1 3]中,HMGB1中A-box构象改变导致甲基化,其结合DNA的活性明显降低,这一改变导致HMGB1由胞核进入胞质中,同时B-box上Lys112的单一甲基化也可使HMGB1发生核转位进入胞质。所以HMGB1可作为染色质组中甲基化药物作用靶点。
2.4 磷酸化磷酸化HMGB1与DNA结合/弯曲、胞核-胞质分布及释放有密切关系[14]。在体外实验中,PKC-磷酸化的HMGB1增加结肠癌细胞HMGB1的释放[15]。
2.5 氧化越来越多的证据表明HMGB1的定位及功能大部分取决于氧化修饰[6]。HMGB1一级结构内的Cys23/Cys45/Cys106,是氧化修饰的核心靶向氨基酸[16],这3个半胱氨酸可被多种氧化信号氧化成以下几种形式:氧化硫醇侧链(R-SH)、二硫酸盐(R-S-S-SH)、硫磺酸(R-SOH)、磺酸跟(R-SO3H)及全部硫醇型(R-SH-SH-SH),氧化后的HMGB1与非氧化HMGB1相比,与DNA结合变疏松,有利于释放至胞质、胞外。在活化的免疫细胞和损伤细胞中,最常见的氧化信号-活性氧(ROS)使HMGB1不同程度被氧化,在核内结合DNA紧密性下降从而促进HMGB1的转位和释放;同时,氧化修饰还影响HMGB1在细胞外的活动,包括免疫、自噬、炎性反应、肿瘤细胞生长、侵袭和转移及趋药性[17, 18]:(1)当ROS较少时,初级氧化型(R-SH) HMGB1分泌至胞外与RAGE结合,诱导周围肿瘤细胞发生自噬或调节细胞的迁移、生长和蛋白表达[19],使细胞适应各种不利环境。细胞自噬正反馈诱导更多HMGB1的胞外转移发挥作用。(2)当ROS增加、氧化损伤加重时,细胞发生凋亡。从氧化敏感的线粒体中释放的细胞色素C可进一步激活凋亡通路诱导凋亡;在凋亡晚期,氧化型HMGB1(R-SO3H)被释放,作为免疫抑制因子诱导树突状细胞的免疫耐受[20],如果HMGB1被Caspase1裂解并结合RAGE后,这一过程可被逆转[21];同时HMGB1(R-SO3H)可能有诱导凋亡的作用。(3)当ROS非常多,氧化损伤非常严重时,细胞坏死,细胞线粒体渗透性转变(MPT)或线粒体膜破裂,细胞崩解,此时两种形式的HMGB1渗漏至胞外:①二硫酸盐型HMGB1(S-S-SH),它与TLR4/MD2结合产生一系列细胞因子,促进炎性反应[22];②全部硫醇型HMGB1(SH-SH-SH),作为一趋化因子与CXCL12形成络合物后与CXCL4结合诱导趋化因子的生成,产生趋药性[19, 22]。
3 HMGB1与肿瘤相关的细胞定位及其功能 3.1 细胞核内功能(1) DNA伴侣:参与DNA复制、结合、损伤修复[23];维持端粒及染色体稳定性[24, 25];(2)调节多个靶向基因的转录[2];(3)通过调节HMGB1的转录调节自噬和凋亡[19]。
3.2 细胞质内功能(1)氧化还原反应传感器[6];(2)依赖外源性HMGB1调节细胞自噬,使细胞逃逸、免疫耐受、耐受化疗或放疗[19];(3)以出胞方式释放HMGB1[26]。
3.3 细胞外液功能氧化修饰后相关DAMP信号通路[17]:(1)简化型(R-SH):与RAGE结合,诱导周边细胞的发生依赖Beclin-1的自噬、对放疗或化疗耐药、或促进细胞的迁移、生长;(2) HMGB1(R-SO3H):作为免疫抑制因子诱导树突状细胞的免疫耐受,使肿瘤细胞逃过免疫反应,促进肿瘤发生;但也可结合RAGE诱导细胞凋亡,增加化疗及放疗细胞毒性;(3)二硫酸盐型HMGB1(S-S-SH):它与TLR4/MD2结合产生一系列细胞因子,促进炎性反应,促进侵袭和转移;(4)硫醇型HMGB1(SH-SH-SH):趋药活性,招募白血球,增加药物毒性,促进细胞死亡。
其他功能:(1)增强由巨噬细胞激活的NK细胞的IFN-γ的释放[27];(2)与其他细胞因子协同调节细胞功能[28];(3)与DC细胞的TIM3结合,降低抗肿瘤免疫反应[29]。
4 HMGB1与肿瘤 4.1 HMGB1与肾细胞癌在肾透明细胞癌中HMGB1表达增加[12]。HMGB1-RAGE通路通过激活ERK1/2在肾透明细胞癌进程中起促进作用[30]。
4.2 HMGB1与肺癌在非小细胞肺癌(NSCLC)中,HMGB1表达增加与疾病的进展、侵袭和转移有关,血清HMGB1水平可能成为NSCLC的生物标志物[31]。miR-218在肺癌中作为肿瘤抑制剂通过部分下调HMGB1表达从而减少转移[32]。HMGB1通过激活PI3K-AKT和NF-κB通路调节肺癌细胞MMP-9表达和细胞转移能力[33]。
4.3 HMGB1与胰腺癌在胰腺癌中血清HMGB1升高,化学药物治疗后也可见升高[34],从坏死细胞或免疫细胞释放的HMGB1通过结合RAGE促进ATP生成和胰腺癌细胞生长[35]。用RNA干扰技术或反义核苷酸沉默HMGB1或其受体RAGE可以抑制胰腺癌细胞的侵袭,通过降低自噬增加化疗药物的敏感度[36, 37, 38]。其受体RAGE的缺失可抑制致瘤基因K-RAS所致的胰腺癌变。这些研究提示HMGB1-RAGE通路在胰腺癌生长和治疗中起关键调节作用[36]。
4.4 HMGB1与胃癌在胃癌中,HMGB1mRNA和蛋白的表达均增高且与炎性状态有关。血清HMGB1水平是早期诊断胃癌的标志物[39]。HMGB1及RAGE的同时高表达加强NF-κB的活性促进胃癌的侵袭和转移[40, 41]。在化疗中,HMGB1介导的细胞自噬降低长春新碱引起的细胞凋亡,部分原因是通过上调Mcl-1,Mcl-1可使肿瘤细胞逃避凋亡[42]。然而,在抗癌治疗后,HMGB1的高表达却是预后良好因素[43]。这些结果提示HMGB1在胃癌的不同阶段发挥着不同的作用。
4.5 HMGB1与结肠直肠癌基因突变(APC、K-RAS、p53)、染色体不稳定、DNA修复力差和异常DNA甲基化被认为是结肠直肠癌发病的分子遗传基础,核内HMGB1可能是这些分子遗传基础的重要调节因子[44]。在结肠直肠癌患者中,HMGB1与肿瘤进展、迁移和预后差有关[45, 46, 47, 48];放射性栓塞治疗后HMGB1表达增加预示着疗效差[46]。腹部手术创伤后HMGB1的大量分泌促进结直肠癌术后腹膜转移[49]。坏死结肠癌细胞释放的HMGB1通过RAGE通路加强剩余肿瘤细胞的再生和转移[50]。在早期研究中提示细胞外HMGB1诱导巨噬细胞凋亡、阻止巨噬细胞浸润至结肠癌组织中,从而减弱宿主抗癌的免疫力[51],但另有研究提示奥沙利铂、氟尿嘧啶等化疗致肿瘤细胞释放的HMGB1可通过TLR4通路激活树突状细胞(DCs),然后加强T细胞的抗肿瘤免疫反应[52, 53]。在结肠癌中,沉默HMGB1增加化疗敏感度,部分原因可能是HMGB1下调后,p53介导的自噬和凋亡增加了[54]。Kikuchi等将能分泌HMGB1拮抗剂的间充质干细胞(MSCs)治疗荷瘤小鼠,肿瘤明显减少,提示着自体骨髓来源细胞有望成为一种新的治疗策略[55]。HMGB1的靶向治疗研究显示,应用RNA干扰、EP (丙酮酸乙酯)、乙酰半胱氨酸抑制HMGB1表达、释放和活性,可以抑制结肠癌转移性肝癌模型的肿瘤生长[56, 57]。
4.6 HMGB1与原发性肝癌(HCC)血清HMGB1水平在HCC患者中升高,并且HMGB1在肝脏的表达与肝癌病理分级、远处转移、耐药密切相关[58, 59, 60, 61]。在感染HCV或HBV的HCC患者中血清HMGB1比单纯的HCC患者明显升高[61]。低氧的肿瘤微环境释放HMGB1可与TLR4和RAGE结合,激活NFkB、AKT和炎性通路,促进HCC的侵袭和转移[57, 58, 59, 60, 61]。p53一般为肿瘤抑制因子,但在发展为肝癌过程中可能是HMGB1释放的正调节因子[62]。这些研究提示HMGB1在HCC的发展过程和治疗中起着关键性作用。
4.7 HMGB1与乳腺癌人类乳腺干细胞(CSCs)表面高表达TLR2和其配体HMGB1,介导CSCs的自我更新、肿瘤发生和转移能力[63]。对新辅助化疗有反应(CR或PR)的乳腺癌患者HMGB1升高,而治疗效果差(SD或PD)的患者新辅助化疗后HMGB1没有升高,表明早期动态变化的血清HMGB1水平可能是预测乳腺癌新辅助化疗最终效果的早期预测因子[64, 65]。体外实验中,miR-200c能抑制HMGB1表达从而减少乳腺癌细胞的侵袭和转移[66]。联合化疗导致转移性乳腺癌细胞释放的HMGB1介导了对肿瘤细胞起杀伤作用的自身免疫反应的激活[67]。这些研究提示可将HMGB1作为判断肿瘤治疗疗效的指标,并可能成为有价值的基因治疗靶点
4.8 HMGB1与前列腺癌在前列腺癌患者中,HMGB1和RAGE表达的增高与肿瘤进展及预后差相关,提示着RAGE和HMGB1可作为前列腺癌新的预后指标[68]。根治性前列腺癌术后高表达HMGB1提示预后差[69]。利用RNAi沉默HMGB1的配体RAGE可诱导肿瘤细胞凋亡、抑制肿瘤的生长[70]。大鼠前列腺癌形成过程中,HMGB1引发适应性免疫反应促进肿瘤的形成,提示着HMGB1可作为肿瘤预防和治疗的靶点[71]。
4.9 HMGB1与宫颈癌在宫颈上皮鳞状细胞癌(CSCC)患者中,HMGB1高表达与肿瘤侵袭和转移显著相关,HMGB1/RAGE通路在CSCC转移中起关键作用[72]。复发CSCC患者血清HMGB1水平明显高于无复发CSCC患者和健康对照组者,血清HMGB1可成为评估CSCC患者肿瘤复发和预测预后的因子,与其他因子联合检测可提高诊断特异性[73]。
4.10 HMGB1与血液恶性肿瘤在血液系统恶性疾病治疗过程中HMGB1可过表达,促进恶性细胞增殖,进而降低疗效;HMGB1与Beclin1、ERK、JNK等蛋白相互作用促进血液恶性肿瘤细胞自噬(外源性HMGB1则直接诱导自噬),参与化疗放疗抵抗。因此,通过抑制HMGB1表达,促进肿瘤细胞凋亡及增加血液病细胞对化疗药物的敏感度,是治疗血液恶性肿瘤的新策略[74]。动态变化HMGB1也可作为非霍奇金淋巴瘤(ALL)治疗效果的早期预测因子[75]。
4.11 HMGB1与黑色素瘤在黑色素瘤患者中,黑色素瘤标本中HMGB1表达明显高于正常组织或黑色痣组织,并且更高水平HMGB1与分级更高、预后更差相一致。进一步实验证明HMGB1在黑色素瘤中有着致瘤原性,有望成为黑色素瘤治疗靶点之一[76]。
5 结论及展望HMGB1最早报道于1973年,随着研究地深入,越来越多的功能被发现:从非组蛋白染色质结合蛋白到晚期、早期炎性因子,再到对肿瘤的双刃剑作用,尤其是近15年里,HMGB1的转录后修饰、定位及一系列受体被发现,细胞内外的HMGB1在肿瘤的发生发展中起着明显不同的作用,这些特性使其成为一个有意义的生物标志及治疗靶点[77]。许多针对HMGB1的肿瘤治疗研究如抑制HMGB1释放及活性正在进行中[78]。在鼠类模型HMGB1的条件性敲除研究中,得到了有关HMGB1在肿瘤作用中复杂甚至相反的结论[11, 79, 80]。未来在HMGB1定位、结构、转录后修饰及相关作用分子的研究,将解开HMGB1在肿瘤发生发展中复杂作用之谜。
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