程 利 何勇勇 综述 唐 亮 审校
(安徽省宣城市人民医院普外一科,宣城 242000)
文献综述·
鞘氨醇激酶在肿瘤中的作用
程 利 何勇勇 综述 唐 亮 审校
(安徽省宣城市人民医院普外一科,宣城 242000)
鞘氨醇激酶是一种癌基因,能够促进恶性肿瘤细胞生长和抑制其凋亡,抑制剂的使用能够使肿瘤细胞加速凋亡。高表达鞘氨醇激酶的恶性肿瘤患者有较短的生存期和较高的复发率,而低表达者患者生存期较长。鞘氨醇激酶抑制剂的使用可以提高患者生存率和降低复发率。鞘氨醇激酶是恶性肿瘤患者预后的有用指标,可以作为治疗恶性肿瘤患者的一个有效的靶点。本文对鞘氨醇激酶对恶性肿瘤患者预后的影响做一综述。
鞘氨醇激酶; 恶性肿瘤
鞘磷脂代谢产物在肿瘤细胞的新陈代谢中扮演重要角色,其中磷酸鞘氨醇(sphingosine-1-phosphate,S1P)促进细胞生存与增殖,与之相反,神经酰胺(ceramide)和鞘氨醇(sphingosine,SP)促使细胞生长停滞和凋亡。这些脂类代谢产物在细胞中可以相互转换,它们之间的平衡调节着细胞的增殖、存活和凋亡。鞘氨醇激酶(sphingosine kinase,SPHK)是这个平衡的关键酶,能够催化SP生成S1P。研究[1]表明SPHK在多种实体肿瘤中均高表达,其基因具有癌基因的特征,保护肿瘤细胞避免凋亡。高表达SPHK患者有较低的生存期和较高的复发率[2]。SPHK抑制剂的应用实现其活性的下调,阻止其在恶性肿瘤中的作用[3]。因此,SPHK蛋白的检测是判断肿瘤患者预后的一个非常有意义的分子标志物,SPHK分子靶向治疗在微创介入领域将会有非常好的应用前景。本文对SPHK在肿瘤预后中的作用做一综述。
Olivera等[4]在1998年首次从大鼠肾脏细胞中提取出SPHK,相对分子质量为49 000。目前,SPHK家族共有7个同工酶被克隆和鉴定。SPHK1和SPHK2源自人类和小鼠,其在酵母和植物中的同源基因也已得到鉴定。在人类中,SPHK1基因位于17号染色体(17q25.2),相对分子质量为42 400,在心脏、脾、肺和大脑大量表达;而SPHK2基因位于19号染色体(19q13.2),相对分子质量为65 000,在脑、肾和肝表达最高。SPHK1和SPHK2基因保守区高度同源,结构也有相同的C1~C4区和羧基端,其中包括保守的甘油二酯激酶ATP结合域。虽然SPHK1和SPHK2显示80%的氨基酸序列相似性,然而它们之间的区别在中部和N′末端,SPHK1缺乏跨膜结构域及识别信号序列;SPHK2在N′末端比SPHK1多240个氨基酸残基且包含几个跨膜结构域,在N′末端拥有核定位信号,一旦与配体结合,就可以阻止信号进入核内从而抑制DNA的合成[5,6]。SPHK1可以被很多的生长4因子激活,包括:血小板衍生生长因子、血管内皮生长因子、血磷脂酸、G蛋白耦联变体(guanosine-binding protein couple receptor,GPCR)配体、磷酸鞘氨醇、类固醇激素、细胞因子、肝细胞生长因子和表皮生长因子等[7,8]。SPHK1的激活机制有3种:①酸性磷脂的相互作用;②与其他蛋白信号分子相偶联;③磷酸化和易位到细胞膜。SPHK1主要存在于细胞液中,激活后易位到细胞膜上催化SP转化为S1P,S1P和S1P受体结合后使细胞发生各种生物活性的改变。
S1P既是细胞内信号传导的第二信使分子,又可以分泌至细胞外,通过细胞表面受体发挥生物学效应。S1P细胞膜受体是内皮分化基因家族(EDG),为GPCR。S1P和S1P受体结合后,可以激活丝裂原活化蛋白激酶、磷脂酰肌醇3激酶和丝氨酸/苏氨酸蛋白激酶等信号途径,从而调节细胞增殖、凋亡、迁移和侵袭等生物效应,并介导血管生成、炎性反应、肿瘤的转移和复发等病理生理过程[9]。
外源性S1P可以促进内皮细胞及多种肿瘤细胞增殖和迁移。S1P对细胞生物活性的影响取决于细胞表面受体亚型。在很多细胞中,激活S1P受体1产生迁移效应,而S1P受体2激活后则产生细胞迁移抑制效应。纤维蛋白溶酶原激活剂和它的受体结合可以促进多形性胶质母细胞瘤细胞侵袭能力,而抑制SPHK1能够减弱这种侵袭能力。S1P和S1P受体1结合可以诱导纤维蛋白溶酶原激活剂系统,这一现象表明S1P的信号转导可以增强多形性胶质母细胞瘤细胞侵袭性[10,11]。S1P与S1P受体2结合对胶质母细胞瘤起到抗迁移效应,RHOA/RHO激酶激活与这种迁移反应有密切关系[12]。S1P受体3在肿瘤细胞迁移中扮演重要角色,S1P受体3激活后促进甲状腺癌细胞迁移。SPHK1过表达使S1P水平升高并且使其与S1P受体1和S1P受体3结合后增加细胞迁移效应[13]。因此,S1P受体亚型的平衡是影响细胞生物学功能的一个重要因素。
大量研究表明SPHK是一种致癌酶类,其激活与抗凋亡、转化、增殖和肿瘤细胞生存密切相关[14~17]。NIH3T3成纤维细胞中SPHK基因过度表达增强细胞增殖和锚定独立增长能力,以及增强NOD/SCID小鼠致瘤性[16]。神经母细胞瘤细胞和乳腺癌细胞内源性SPHK基因表达沉默导致细胞周期停滞[18]。SPHK基因表达下调能够有效抑制裸鼠肿瘤形成[19]。Li等[20]报道SPHK1在胃癌组织和胃癌细胞系中mRNA和蛋白表达量高于正常胃组织和癌旁组织,175例胃癌中161例SPHK1 mRNA和蛋白呈高表达状态,阳性率为92%,并且与早期胃癌预后有密切相关性,高表达SPHK1胃癌患者5年生存率为23.85%,低表达SPHK1患者5年生存率为49.66%(P=0.0019)。Liu等[21]对159例唾液腺癌研究显示,高表达SPHK1的唾液腺癌患者5年生存率为46.3%,低表达SPHK1患者5年生存率为93.4%(P=0.001)。Ruckhäberle等[22]对750例乳腺癌研究表明,高表达SPHK1患者5年生存率为64.9%,低表达SPHK1患者5年生存率为75.8%(P<0.05)。最近的研究表明溶血磷脂酸(lysophosphatidic acid,LPA)在胃癌细胞迁移和侵袭中扮演着重要角色,能够促进SPHK1在胃癌中高表达,促进胃癌细胞迁移和侵袭能力,多因素分析显示SPHK1是胃癌预后的独立危险因子[23]。此外,Cho等[24]研究表明SPHK1参与调控前列腺癌细胞生长、存活、侵入、血管生成和肿瘤发生,利用调节低氧诱导因子1α下调SPHK1活性使前列腺癌细胞生长和浸润得到有效控制。Tan等[25]基础和临床试验表明,SPHK1在结肠癌中起着重要作用,他们的试验研究表明SPHK1抑制剂的使用降低了结肠癌细胞生存能力,也增加了化疗药物5-FU的敏感性,提示SPHK1抑制剂可以作为化疗药物辅助剂,随后的临床试验也证实SPHK1高表达的结肠癌患者5年复发率为71.28%,低表达的结肠癌患者5年复发率为24.66%(P=0.042);高表达SPHK1的结肠癌患者5年生存率为37.1%,低表达SPHK1的结肠癌患者5年生存率为62.9%(P<0.05)。综上所述,SPHK1是很多恶性肿瘤预后的独立影响因子。
SPHK1对肿瘤复发和预后有至关重要的作用,SPHK1抑制剂的使用可以有效抑制肿瘤生长,例如SPHK1抑制剂SK1-I能够抑制人白血病细胞复制,加速其凋亡[26]。Fuereder等[27]研究表明SPHK1抑制剂的使用能够使胃癌细胞凋亡加快并且抑制胃癌细胞生长(P<0.05)。Ruckhäberle等[28]临床研究表明SPHK1抑制剂的使用可以下调乳腺癌中SPHK1表达,并且对乳腺癌的治疗有良好作用,SPHK1抑制剂组5年生存率为26.7%,非SPHK1抑制剂组5年生存率5.8%(P=0.042)。Pchejetski等[29]研究表明SPHK1抑制剂FTY720能够抑制前列腺肿瘤生长,FTY720治疗后患者5年生存率为40%,非治疗组患者生存率为28%(P<0.05)。神经酰胺、SP和S1P作为能够相互转化的脂类代谢产物现在已经被公认为是调节细胞生物活性的重要物质,参与细胞的生理和病理过程[30]。这些年对鞘磷脂类物质在细胞中作用研究越来越多,神经酰胺和SP已被证明与细胞周期停滞和细胞凋亡有关,而S1P参与细胞增殖、存活、迁移、血管生成和分化[31]。神经酰胺、SP和S1P在细胞中水平与SPHK激活有密切关联。当细胞受到相关刺激的时候,细胞中SPHK被激活,催化SP转换成S1P,这样细胞中的S1P水平升高;相反,当SPHK活性受到抑制,细胞中神经酰胺、SP水平升高,而S1P水平降低,这种动态平衡被称为“鞘类变阻器”[32],在细胞的生存和凋亡中起关键作用,在这个平衡中,SPHK是关键限速酶。很多证据表明SPHK是一个潜在治疗靶点:①SPHK基因本身就是一个癌基因;②SPHK在很多肿瘤细胞中都是过表达;③很多生长因子和有丝分裂原能够双向激活SPHK,使细胞内S1P水平升高;④SPHK能够刺激肿瘤血管的生成;⑤SPHK和S1P本身就可以刺激细胞的移动,与肿瘤细胞的侵袭和转移有密切关系;⑥肿瘤的放疗和化疗效果减弱与SPHK水平升高有关,抑制SPHK能够使这些治疗效果增加;⑦SPHK、S1P和受体酪氨酸蛋白激酶提供了一个复杂的串扰网络,SPHK是这个网络调节循环中一个重要因素,它可以将肿瘤信号放大;⑧SPHK是“鞘类变阻器”控制器,抑制SPHK不仅可以抑制S1P产生,还可以使细胞中神经酰胺和SP增加,使肿瘤细胞走向死亡。由此可见,SPHK1可以作为治疗恶性肿瘤的潜在靶点。
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(修回日期:2015-02-09)
(责任编辑:李贺琼)
Role of Sphingosine Kinase on Tumors
ChenLi,HeYongyong,TangLiang.
DepartmentofGeneralSurgeryWardⅠ,XuanchengPeople’sHospitalofAnhui,Xuancheng242000,China
Correspondingauthor:HeYongyong,E-mail:heyongyong84@sina.com
【Summary】 Sphingosine kinase (SPHK) is an oncogene promoting tumor cell growth and inhibiting apoptosis. Inhibitors of SPHK promote tumor cell apoptosis. Patients with higher SPHK expression have shorter overall survival time and higher recurrence rates, whereas those with lower SPHK expression survives longer. Inhibitors of SPHK can improve survival and reduce recurrence rates. SPHK is a useful marker for the prognosis of malignant tumors, and it could be an effective target for treating malignant tumors. This article is to investigate effects of SPHK on the prognosis in patients with malignant tumors.
Sphingosine kinase; Malignant tumor
,E-mail:heyongyong84@sina.com
R730.53
A
1009-6604(2015)09-0840-04
10.3969/j.issn.1009-6604.2015.09.021
2014-05-21)