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骨肉瘤相关分子机制研究进展

2017-02-27张明胡向阳杜远立

海南医学 2017年11期
关键词:癌基因成骨细胞分化

张明,胡向阳,杜远立

(三峡大学人民医院·宜昌市第一人民医院骨科,湖北宜昌443000)

骨肉瘤相关分子机制研究进展

张明,胡向阳,杜远立

(三峡大学人民医院·宜昌市第一人民医院骨科,湖北宜昌443000)

骨肉瘤是临床常见的骨科恶性肿瘤之一,其侵袭力强,可早期转移,预后差。近年来,对于骨肉瘤的相关信号通路及分子机制研究愈发收到学者的重视,且对于信号通路、分子机制的研究也为骨肉瘤的治疗提供了更多的可能。本文主要从细胞信号通路,抑癌基因、癌基因表达失衡,成骨细胞分化缺陷三部分介绍骨肉瘤相关分子机制研究进展。

骨肉瘤;分子机制;信号通路;癌基因

骨肉瘤(osteosarcoma,OS)是青少年中最常见的恶性肿瘤之一。随着新辅助化疗、手术治疗及综合治疗的不断进步,骨肉瘤5年生存率已达到60%~70%,但由于骨肉瘤细胞侵袭力强,早期就可经血运转移,且易产生耐药,其5年生存率仅为50%,预后较差,病死率较高。虽然导致骨肉瘤发生、发展的分子机制尚未完全阐明,但不断有报道显示胞内信号通路异常,癌基因、抑癌基因表达失衡及成骨细胞分化缺陷在骨肉瘤发生发展过程中起到重要作用,本文就上述内容做一综述。

1 细胞信号通路异常

当细胞受到某种胞外刺激后,需要将这一刺激产生的信息传入胞内,致使细胞依据刺激产生的信息做出一定反应,这一传递信息的路径称之为细胞信号通路。细胞信号传导异常在骨肉瘤的发生、发展过程中起到了非常重要的作用。胰岛素样生长因子(IGF)信号轴在青少年时期骨发育阶段与骨肉瘤关系密切。正常的IGF信号轴由胰岛素样生长因子配体激活IGF-1受体(IGF-1R)后,激活的IGF-1R可以刺激细胞增殖、蛋白合成、葡萄糖代谢,同时还能抑制细胞凋亡[1]。最近研究发现IGF信号轴调控缺失与肿瘤的转移有着密切的关联[2]。Jentzsch等[3]和Wang等[4]研究发现预后较差的骨肉瘤患者中,其IGF-1与IGF-1R表达量增高。此外,Shimizu等[5]在研究中还发现,胰岛素样生长因子2 (IGF-2)可以通过一种自噬休眠状态介导肿瘤细胞耐药,使细胞不被化疗药物杀伤。IGF信号轴下游媒介,如IGF、胰岛素信号通路、胰岛素受体底物1(insulin receptor substrate 1,IRS-1)对于间充质干细胞(mesenchymal stem cells,MSCs)的分化都非常重要。报道显示,在OS中,IGF结合蛋白(IGF binding proteins,IGFBPs)通过IGF依赖、IGF非依赖性机制调节IGF信号轴。Contaldo等[6]发现下调上述调控媒介可导致OS细胞向恶性转化。IGF结合蛋白5(IGF binding proteins 5,IGFBP-5)在许多细胞系中明显下调。Luther等[7]和Su等[8]研究显示,外源性给予IGFBP-5可以通过多种机制抑制肿瘤生长及转移。

IGF-1R下游信号经由磷脂酰肌醇3激酶/蛋白激酶B(phosphatidylinositol 3-kinase/protein kinase B,PI3K/AKT)、Ras/MAPK/ERK信号级联通路(reticular activating system,Ras,网状激活系统;mitogen-activated protein kinases,MAPK,丝裂原活化蛋白激酶;extracellular regulated protein kinases,ERK,细胞外调节蛋白激酶)传递[9]。PI3K/AKT与OS发病机制已被证实有显著关联。Zhang等[10]研究证实上调PI3K/AKT表达,可以促进OS细胞增殖、增强侵袭力,并减少肿瘤细胞凋亡。研究发现,多种分子可促使OS细胞产生上述改变,包括长链非编码RNA(long noncoding RNA,LncRNA)、肺腺癌转移相关转录子1(metastasis-associated lung adenocarcinoma transcript 1,MALAT1)、肿瘤坏死因子受体相关因子4(tumor necrosis factor receptor-associated factor 4,TRAF4)、自噬相关蛋白6(autophagy related protein 6,Beclin-1)[11]。抑制PI3K/AKT活性不仅可减弱肿瘤侵袭力,还可以逆转细胞耐药性[12-13]。陈倩竹等[14]在研究中发现下调异质核核糖核蛋白A2/B1(heterogeneous-nuclear ribonucleoprotein A2/ B1,hnRNPA2/B1)表达能够抑制骨肉瘤细胞的生长,其机制可能涉及Akt信号通路的调控。Niu等[15]和Zhu等[16]研究表明Aurora-A、Aurora-B激酶抑制剂可抑制PI3K/AKT活性。周云飞等[17]研究发现Let-7a/g/i可负向调控Aurora-B在骨肉瘤细胞中的表达。TAp73抑癌基因p53家族的成员之一。许遵营等[18]研究发现人骨肉瘤中抑癌基因TAp73可与骨肉瘤中自噬相关因子Beclin1依赖的肿瘤自噬活性上调有关,检测TAp73和Beclin1在人骨肉瘤中的表达水平可有助于患者临床预后判断。

Bianchi等[19]研究显示炎症及细胞因子信号通路与OS发生有着密切的关联。Zhang等[20]研究发现转化生长因子β(transforming growth factor β,TGF-β)不仅在OS细胞向肿瘤干细胞分化中起重要作用,且与肿瘤侵袭、放化疗、预后呈密切关联。另一项研究显示,肿瘤细胞中通常能够发现自分泌信号途径,TGF-β还能通过激活MAPK信号通路增加OS细胞的迁移能力[21]。同样,肿瘤坏死因子α(tumor necrosis factor α,TNF-α)与OS播散有密切关联,尽管最近有报道TNF-α的单克隆抗体抑制剂英夫利昔单抗(Infliximab)在小鼠模型中可以抑制OS细胞运动和肺转移[22]。

白细胞介素(IL)是另一类在OS发生、发展过程中有重要作用的细胞因子。Zhou等[23]研究发现促炎性细胞因子IL-32,呈剂量依赖性激活AKT信号通路及上调基质金属蛋白酶13(matrix metalloproteinase 13,MMP13)的表达,从而增强细胞侵袭、转移能力。TNF-α、IL-1β调节OS细胞中IL-34的表达,IL-34通过促进肿瘤新生血管的形成及召集肿瘤相关巨噬细胞促进肿瘤转移,而肿瘤相关巨噬细胞能够产生更多TGF-β并促进肿瘤生长[24-25]。研究也发现,IL-11受体是多种肿瘤患者长期预后不良的指标,其在骨肉瘤患者亦呈过表达[26]。

单核细胞趋化蛋白1(monocyte chemoattractant protein 1,MCP-1或CCL2)是可以刺激巨噬细胞释放小分子的一类趋化因子,而后者可以召集更多的炎性细胞来此维持肿瘤的侵袭性。研究显示,MCP-1在单核细胞穿过血管内皮进入组织的过程中发挥作用[27]。也有学者研究表明在OS中,MCP-1表达明显上调,且能激活AKT信号通路。敲除MCP-1基因后,OS细胞增殖及侵袭能力明显受限。白细胞介素、JAK2/STAT3信号通路等在OS发生、发展中也发挥了一定作用[28]。体内外实验证明使用JAK2/STAT3抑制剂能够阻滞OS细胞生长,Yan等[29]和Liu等[30]在研究中通过抑制STAT3短发夹RNA也得到了相类似的结果。

2 抑癌基因、癌基因表达失衡

癌基因(oncogene)是指其激活后会引起细胞癌变的基因,抑癌基因是指在正常细胞中存在,激活后具有细胞增殖作用,但缺失或被抑制后期抑癌作用减弱或消失的基因。与其他肿瘤相类似,癌基因、抑癌基因表达失衡是骨肉瘤发生、发展的重要机制之一。与肿瘤复发密切相关的c-Myc是骨肉瘤中研究最广泛和深入的癌基因之一,其在骨肉瘤中过表达量超过10%。Han等[31]和Wu等[32]在研究中已经确认c-Myc可以通过激活MEK-ERK通路和减少细胞凋亡、增加OS细胞的侵袭力。有文献报道,c-Myc活性被抑制后,OS细胞增殖、侵袭及细胞活性减弱[33]。与c-Myc类似,c-Fos也是一种癌基因,其在原发肿瘤中表达上调与肿瘤转移率呈正相关。Liu等[34]研究表明,在OS等细胞中通过下调,c-Fos可以抑制OS细分化。Walter等[35]在另一项研究中下调细胞周期调节相关的癌基因S100A4,也可以抑制OS细胞凋亡及分化。

史继德等[36]在研究中证实IRX2(iroquois homebox 2)基因可部分通过JAK3/STAT5信号通路调控骨肉瘤细胞的增殖。仇超等[37]在研究中发现抑制ID1基因表达可以逆转骨肉瘤的恶性生物学行为并诱导骨肉瘤细胞发生骨转化。沉默多聚核苷酸激酶/磷酸酶(polynucleotide kinase/phosphatase,PNKP)不仅可以增加骨肉瘤细胞放射治疗的敏感性,使细胞周期停滞在S期,还能促进细胞凋亡、降低线粒体膜电位水平[38]。癌基因Eag在MG-63细胞中高表达,其参与骨肉瘤细胞增殖,且受到p38 MAPK/p53信号通路的调控[39];另有报道特异性沉默Eag1基因、过表达肿瘤坏死因子相关凋亡诱导配体(TNF-related apoptosis-inducing ligand,TRAIL)可产生协同抗骨肉瘤作用[40]。

Yu等[41]研究表明转录因子MEF2D过表达时可以通过miRNA作用于细胞周期G2/M从而抑制细胞增殖。近期实验表明,编码Aurora-A激酶的基因AURKA是一致癌基因,同时亦是重要的有丝分裂调节因子[42]。沉默AURKA或抑制Aurora-A激酶活性不仅通过引起细胞超倍体和凋亡,而且在OS耐药细胞株中能与传统化疗药物协同作用,起到良好的协同杀伤效果[43]。而OS分子生物学机制真正的复杂性在于,在OS中起作用的癌基因、抑癌基因被不断报道。这些新发现的癌基因、抑癌基因包括:PAK7(p21-activated kinase 7,p21活化激酶7)、E2F2(E2F transcription factor 2,E2F转录因子2)、SATB1(special AT-rich sequence-binding Protein-1,富含AT序列结合蛋白1)及一些microRNA(如miRNA-301a)。上述新发现的癌基因、抑癌基因在OS发病机制中的具体作用仍有待深入研究。

3 成骨细胞分化缺陷

骨组织的成型与生长其实是骨祖细胞、成骨细胞、骨细胞及破骨细胞之间的动态平衡。而骨肉瘤好发于青少年原因之一可能是,青少年时期骨转化水平高,成骨相关的细胞分化缺陷容易被放大[44]。成骨细胞来源于MSCs,而未分化的骨髓基质细胞具有自我更新及向骨、肌肉、肌腱、脂肪分化的潜力。内源性或外源性环境因素可以影响MSCs向成骨细胞转化。内、外微环境失调或受到其他刺激(如促肿瘤炎症细胞因子)引起细胞增殖与分化失衡,最终导致恶性肿瘤的发生。

成骨细胞与骨肉瘤细胞不仅在细胞增生性、抗凋亡及其基因表达谱上有高度相似性,且二者都能表达碱性磷酸酶(ALP)、结缔组织生长因子(CTGF)。成骨细胞系、未分化或侵袭性较小的肿瘤细胞中存在细胞分化缺陷。研究发现,在高度侵袭性的OS细胞中,骨钙素(OCN)、骨桥蛋白(OPN)表达量较低,但二者在成熟的成骨细胞中表达量较高[45]。OS细胞可以通过通过端粒的替代延长(alternative lengthening of telomeres,ALT)抗衰老晚期成骨细胞,而成骨细胞则不具备这一能力。大多数终末分化的成骨细胞因复制次数增多而导致端粒缩短,OS细胞通过ALT方式使其保持类干细胞状态及应对外源性刺激。

骨形成蛋白(BMPs)代表了一类对OS细胞刺激因子。一般认为BMPs能够促进MSCs向成骨细胞系分化。现有报道证实BMPs不仅能够诱导OS细胞的分化,更能够增强OS细胞侵袭性。这主要是因为转录因子Rnux2的低表达。Runx2能能够通过调节BMP活性来阻滞细胞周期及促进细胞终末分化。然而Martin等[46]研究表明RUNX2基因的过表达与骨肉瘤患者预后呈负相关,提示RNUX2的表达对成骨细胞的调控有密切关联。

BMPs是通过Wnt糖蛋白信号通路发挥作用。Wnt糖蛋白信号通路已经被证实能够发挥抑制成骨细胞分化的作用[47]。Wnt信号通路异常可通过典型与非典型的β-catenin通路致使细胞分化及迁移能力增加[48]。除BMPs、Runx2及Wnt外,又不断发现可以促进OS细胞分化的蛋白。这些蛋白包括核受体家族的超级蛋白PPARγ、视黄醇、雌激素等,研究证实上述蛋白可以抑制细胞增殖、提高OS细胞对凋亡易感性[49]。p21是一种促凋亡细胞周期调控因子,调控成骨细胞分化及凋亡,核受体激动剂-1,25-二羟维生素D3(D3[1,25(OH) 2D3]),通过上调能够p21表达水平[50]。总结上述研究不难发现细胞分化缺失在骨肉瘤发生过程中发挥关键作用。

4 小结

综上所述,骨肉瘤发病机制的研究在分子生物学领域愈发广泛和深入,使得未来对于骨肉瘤治疗有更多的可能。随着研究的深入,可以更好的理解不同信号通路与细胞分化途径之间的联系,也就为发现在骨肉瘤发生、发展中起关键作用的信号通路、分子提供了可能,进而也就能针对这些信号通路、分子设计出更加高效低毒的抗肿瘤药物,提高骨肉瘤患者生活质量,改善预后。

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Research progress in molecular mechanism of osteosarcoma.

ZHANG Ming,HU Xiang-yang,DU Yuan-li.
Department of Orthopedics,the First People's Hospital of Yichang(The People's Hospital of China Three Gorges University), Yichang 443000,Hubei,CHINA

Osteosarcoma(OS)is one of the common malignant tumors in Department of Orthopedics.It has strong invasion ability,and early metastasis and poor prognosis.In recent years,studies regarding the signaling pathways and molecular mechanisms of osteosarcoma have

more and more attention among the scholars,which also provides more possibilities for the treatment of osteosarcoma.This article introduces the osteosarcoma related molecular mechanisms mainly from the cell signaling pathway,tumor suppressor gene and oncogene expression imbalance,and osteogenic differentiation defect.

Osteosarcoma(OS);Molecular mechanisms;Signaling pathway;Oncogene

R738

A

1003—6350(2017)11—1826—04

2016-09-12)

10.3969/j.issn.1003-6350.2017.11.035

湖北省卫生计生委西医类一般项目(编号:WJ2015MB172)

杜远立。E-mail:Duyuanli2008@163.com

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