張明，胡向陽(yáng)，杜遠(yuǎn)立

(三峽大學(xué)人民醫(yī)院·宜昌市第一人民醫(yī)院骨科，湖北宜昌443000)

骨肉瘤相關(guān)分子機(jī)制研究進(jìn)展

張明，胡向陽(yáng)，杜遠(yuǎn)立

(三峽大學(xué)人民醫(yī)院·宜昌市第一人民醫(yī)院骨科，湖北宜昌443000)

骨肉瘤是臨床常見(jiàn)的骨科惡性腫瘤之一，其侵襲力強(qiáng)，可早期轉(zhuǎn)移，預(yù)后差。近年來(lái)，對(duì)于骨肉瘤的相關(guān)信號(hào)通路及分子機(jī)制研究愈發(fā)收到學(xué)者的重視，且對(duì)于信號(hào)通路、分子機(jī)制的研究也為骨肉瘤的治療提供了更多的可能。本文主要從細(xì)胞信號(hào)通路，抑癌基因、癌基因表達(dá)失衡，成骨細(xì)胞分化缺陷三部分介紹骨肉瘤相關(guān)分子機(jī)制研究進(jìn)展。

骨肉瘤；分子機(jī)制；信號(hào)通路；癌基因

骨肉瘤(osteosarcoma，OS)是青少年中最常見(jiàn)的惡性腫瘤之一。隨著新輔助化療、手術(shù)治療及綜合治療的不斷進(jìn)步，骨肉瘤5年生存率已達(dá)到60%～70%，但由于骨肉瘤細(xì)胞侵襲力強(qiáng)，早期就可經(jīng)血運(yùn)轉(zhuǎn)移，且易產(chǎn)生耐藥，其5年生存率僅為50%，預(yù)后較差，病死率較高。雖然導(dǎo)致骨肉瘤發(fā)生、發(fā)展的分子機(jī)制尚未完全闡明，但不斷有報(bào)道顯示胞內(nèi)信號(hào)通路異常，癌基因、抑癌基因表達(dá)失衡及成骨細(xì)胞分化缺陷在骨肉瘤發(fā)生發(fā)展過(guò)程中起到重要作用，本文就上述內(nèi)容做一綜述。

1 細(xì)胞信號(hào)通路異常

當(dāng)細(xì)胞受到某種胞外刺激后，需要將這一刺激產(chǎn)生的信息傳入胞內(nèi)，致使細(xì)胞依據(jù)刺激產(chǎn)生的信息做出一定反應(yīng)，這一傳遞信息的路徑稱之為細(xì)胞信號(hào)通路。細(xì)胞信號(hào)傳導(dǎo)異常在骨肉瘤的發(fā)生、發(fā)展過(guò)程中起到了非常重要的作用。胰島素樣生長(zhǎng)因子(IGF)信號(hào)軸在青少年時(shí)期骨發(fā)育階段與骨肉瘤關(guān)系密切。正常的IGF信號(hào)軸由胰島素樣生長(zhǎng)因子配體激活I(lǐng)GF-1受體(IGF-1R)后，激活的IGF-1R可以刺激細(xì)胞增殖、蛋白合成、葡萄糖代謝，同時(shí)還能抑制細(xì)胞凋亡[1]。最近研究發(fā)現(xiàn)IGF信號(hào)軸調(diào)控缺失與腫瘤的轉(zhuǎn)移有著密切的關(guān)聯(lián)[2]。Jentzsch等[3]和Wang等[4]研究發(fā)現(xiàn)預(yù)后較差的骨肉瘤患者中，其IGF-1與IGF-1R表達(dá)量增高。此外，Shimizu等[5]在研究中還發(fā)現(xiàn)，胰島素樣生長(zhǎng)因子2 (IGF-2)可以通過(guò)一種自噬休眠狀態(tài)介導(dǎo)腫瘤細(xì)胞耐藥，使細(xì)胞不被化療藥物殺傷。IGF信號(hào)軸下游媒介，如IGF、胰島素信號(hào)通路、胰島素受體底物1(insulin receptor substrate 1，IRS-1)對(duì)于間充質(zhì)干細(xì)胞(mesenchymal stem cells，MSCs)的分化都非常重要。報(bào)道顯示，在OS中，IGF結(jié)合蛋白(IGF binding proteins，IGFBPs)通過(guò)IGF依賴、IGF非依賴性機(jī)制調(diào)節(jié)IGF信號(hào)軸。Contaldo等[6]發(fā)現(xiàn)下調(diào)上述調(diào)控媒介可導(dǎo)致OS細(xì)胞向惡性轉(zhuǎn)化。IGF結(jié)合蛋白5(IGF binding proteins 5，IGFBP-5)在許多細(xì)胞系中明顯下調(diào)。Luther等[7]和Su等[8]研究顯示，外源性給予IGFBP-5可以通過(guò)多種機(jī)制抑制腫瘤生長(zhǎng)及轉(zhuǎn)移。

IGF-1R下游信號(hào)經(jīng)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信號(hào)級(jí)聯(lián)通路(reticular activating system，Ras，網(wǎng)狀激活系統(tǒng)；mitogen-activated protein kinases，MAPK，絲裂原活化蛋白激酶；extracellular regulated protein kinases，ERK，細(xì)胞外調(diào)節(jié)蛋白激酶)傳遞[9]。PI3K/AKT與OS發(fā)病機(jī)制已被證實(shí)有顯著關(guān)聯(lián)。Zhang等[10]研究證實(shí)上調(diào)PI3K/AKT表達(dá)，可以促進(jìn)OS細(xì)胞增殖、增強(qiáng)侵襲力，并減少腫瘤細(xì)胞凋亡。研究發(fā)現(xiàn)，多種分子可促使OS細(xì)胞產(chǎn)生上述改變，包括長(zhǎng)鏈非編碼RNA(long noncoding RNA，LncRNA)、肺腺癌轉(zhuǎn)移相關(guān)轉(zhuǎn)錄子1(metastasis-associated lung adenocarcinoma transcript 1，MALAT1)、腫瘤壞死因子受體相關(guān)因子4(tumor necrosis factor receptor-associated factor 4，TRAF4)、自噬相關(guān)蛋白6(autophagy related protein 6，Beclin-1)[11]。抑制PI3K/AKT活性不僅可減弱腫瘤侵襲力，還可以逆轉(zhuǎn)細(xì)胞耐藥性[12-13]。陳倩竹等[14]在研究中發(fā)現(xiàn)下調(diào)異質(zhì)核核糖核蛋白A2/B1(heterogeneous-nuclear ribonucleoprotein A2/ B1，hnRNPA2/B1)表達(dá)能夠抑制骨肉瘤細(xì)胞的生長(zhǎng)，其機(jī)制可能涉及Akt信號(hào)通路的調(diào)控。Niu等[15]和Zhu等[16]研究表明Aurora-A、Aurora-B激酶抑制劑可抑制PI3K/AKT活性。周云飛等[17]研究發(fā)現(xiàn)Let-7a/g/i可負(fù)向調(diào)控Aurora-B在骨肉瘤細(xì)胞中的表達(dá)。TAp73抑癌基因p53家族的成員之一。許遵營(yíng)等[18]研究發(fā)現(xiàn)人骨肉瘤中抑癌基因TAp73可與骨肉瘤中自噬相關(guān)因子Beclin1依賴的腫瘤自噬活性上調(diào)有關(guān)，檢測(cè)TAp73和Beclin1在人骨肉瘤中的表達(dá)水平可有助于患者臨床預(yù)后判斷。

Bianchi等[19]研究顯示炎癥及細(xì)胞因子信號(hào)通路與OS發(fā)生有著密切的關(guān)聯(lián)。Zhang等[20]研究發(fā)現(xiàn)轉(zhuǎn)化生長(zhǎng)因子β(transforming growth factor β，TGF-β)不僅在OS細(xì)胞向腫瘤干細(xì)胞分化中起重要作用，且與腫瘤侵襲、放化療、預(yù)后呈密切關(guān)聯(lián)。另一項(xiàng)研究顯示，腫瘤細(xì)胞中通常能夠發(fā)現(xiàn)自分泌信號(hào)途徑，TGF-β還能通過(guò)激活MAPK信號(hào)通路增加OS細(xì)胞的遷移能力[21]。同樣，腫瘤壞死因子α(tumor necrosis factor α，TNF-α)與OS播散有密切關(guān)聯(lián)，盡管最近有報(bào)道TNF-α的單克隆抗體抑制劑英夫利昔單抗(Infliximab)在小鼠模型中可以抑制OS細(xì)胞運(yùn)動(dòng)和肺轉(zhuǎn)移[22]。

白細(xì)胞介素(IL)是另一類在OS發(fā)生、發(fā)展過(guò)程中有重要作用的細(xì)胞因子。Zhou等[23]研究發(fā)現(xiàn)促炎性細(xì)胞因子IL-32，呈劑量依賴性激活A(yù)KT信號(hào)通路及上調(diào)基質(zhì)金屬蛋白酶13(matrix metalloproteinase 13，MMP13)的表達(dá)，從而增強(qiáng)細(xì)胞侵襲、轉(zhuǎn)移能力。TNF-α、IL-1β調(diào)節(jié)OS細(xì)胞中IL-34的表達(dá)，IL-34通過(guò)促進(jìn)腫瘤新生血管的形成及召集腫瘤相關(guān)巨噬細(xì)胞促進(jìn)腫瘤轉(zhuǎn)移，而腫瘤相關(guān)巨噬細(xì)胞能夠產(chǎn)生更多TGF-β并促進(jìn)腫瘤生長(zhǎng)[24-25]。研究也發(fā)現(xiàn)，IL-11受體是多種腫瘤患者長(zhǎng)期預(yù)后不良的指標(biāo)，其在骨肉瘤患者亦呈過(guò)表達(dá)[26]。

單核細(xì)胞趨化蛋白1(monocyte chemoattractant protein 1，MCP-1或CCL2)是可以刺激巨噬細(xì)胞釋放小分子的一類趨化因子，而后者可以召集更多的炎性細(xì)胞來(lái)此維持腫瘤的侵襲性。研究顯示，MCP-1在單核細(xì)胞穿過(guò)血管內(nèi)皮進(jìn)入組織的過(guò)程中發(fā)揮作用[27]。也有學(xué)者研究表明在OS中，MCP-1表達(dá)明顯上調(diào)，且能激活A(yù)KT信號(hào)通路。敲除MCP-1基因后，OS細(xì)胞增殖及侵襲能力明顯受限。白細(xì)胞介素、JAK2/STAT3信號(hào)通路等在OS發(fā)生、發(fā)展中也發(fā)揮了一定作用[28]。體內(nèi)外實(shí)驗(yàn)證明使用JAK2/STAT3抑制劑能夠阻滯OS細(xì)胞生長(zhǎng)，Yan等[29]和Liu等[30]在研究中通過(guò)抑制STAT3短發(fā)夾RNA也得到了相類似的結(jié)果。

2 抑癌基因、癌基因表達(dá)失衡

癌基因(oncogene)是指其激活后會(huì)引起細(xì)胞癌變的基因，抑癌基因是指在正常細(xì)胞中存在，激活后具有細(xì)胞增殖作用，但缺失或被抑制后期抑癌作用減弱或消失的基因。與其他腫瘤相類似，癌基因、抑癌基因表達(dá)失衡是骨肉瘤發(fā)生、發(fā)展的重要機(jī)制之一。與腫瘤復(fù)發(fā)密切相關(guān)的c-Myc是骨肉瘤中研究最廣泛和深入的癌基因之一，其在骨肉瘤中過(guò)表達(dá)量超過(guò)10%。Han等[31]和Wu等[32]在研究中已經(jīng)確認(rèn)c-Myc可以通過(guò)激活MEK-ERK通路和減少細(xì)胞凋亡、增加OS細(xì)胞的侵襲力。有文獻(xiàn)報(bào)道，c-Myc活性被抑制后，OS細(xì)胞增殖、侵襲及細(xì)胞活性減弱[33]。與c-Myc類似，c-Fos也是一種癌基因，其在原發(fā)腫瘤中表達(dá)上調(diào)與腫瘤轉(zhuǎn)移率呈正相關(guān)。Liu等[34]研究表明，在OS等細(xì)胞中通過(guò)下調(diào)，c-Fos可以抑制OS細(xì)分化。Walter等[35]在另一項(xiàng)研究中下調(diào)細(xì)胞周期調(diào)節(jié)相關(guān)的癌基因S100A4，也可以抑制OS細(xì)胞凋亡及分化。

史繼德等[36]在研究中證實(shí)IRX2(iroquois homebox 2)基因可部分通過(guò)JAK3/STAT5信號(hào)通路調(diào)控骨肉瘤細(xì)胞的增殖。仇超等[37]在研究中發(fā)現(xiàn)抑制ID1基因表達(dá)可以逆轉(zhuǎn)骨肉瘤的惡性生物學(xué)行為并誘導(dǎo)骨肉瘤細(xì)胞發(fā)生骨轉(zhuǎn)化。沉默多聚核苷酸激酶/磷酸酶(polynucleotide kinase/phosphatase，PNKP)不僅可以增加骨肉瘤細(xì)胞放射治療的敏感性，使細(xì)胞周期停滯在S期，還能促進(jìn)細(xì)胞凋亡、降低線粒體膜電位水平[38]。癌基因Eag在MG-63細(xì)胞中高表達(dá)，其參與骨肉瘤細(xì)胞增殖，且受到p38 MAPK/p53信號(hào)通路的調(diào)控[39]；另有報(bào)道特異性沉默Eag1基因、過(guò)表達(dá)腫瘤壞死因子相關(guān)凋亡誘導(dǎo)配體(TNF-related apoptosis-inducing ligand，TRAIL)可產(chǎn)生協(xié)同抗骨肉瘤作用[40]。

Yu等[41]研究表明轉(zhuǎn)錄因子MEF2D過(guò)表達(dá)時(shí)可以通過(guò)miRNA作用于細(xì)胞周期G2/M從而抑制細(xì)胞增殖。近期實(shí)驗(yàn)表明，編碼Aurora-A激酶的基因AURKA是一致癌基因，同時(shí)亦是重要的有絲分裂調(diào)節(jié)因子[42]。沉默AURKA或抑制Aurora-A激酶活性不僅通過(guò)引起細(xì)胞超倍體和凋亡，而且在OS耐藥細(xì)胞株中能與傳統(tǒng)化療藥物協(xié)同作用，起到良好的協(xié)同殺傷效果[43]。而OS分子生物學(xué)機(jī)制真正的復(fù)雜性在于，在OS中起作用的癌基因、抑癌基因被不斷報(bào)道。這些新發(fā)現(xiàn)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轉(zhuǎn)錄因子2)、SATB1(special AT-rich sequence-binding Protein-1，富含AT序列結(jié)合蛋白1)及一些microRNA(如miRNA-301a)。上述新發(fā)現(xiàn)的癌基因、抑癌基因在OS發(fā)病機(jī)制中的具體作用仍有待深入研究。

3 成骨細(xì)胞分化缺陷

骨組織的成型與生長(zhǎng)其實(shí)是骨祖細(xì)胞、成骨細(xì)胞、骨細(xì)胞及破骨細(xì)胞之間的動(dòng)態(tài)平衡。而骨肉瘤好發(fā)于青少年原因之一可能是，青少年時(shí)期骨轉(zhuǎn)化水平高，成骨相關(guān)的細(xì)胞分化缺陷容易被放大[44]。成骨細(xì)胞來(lái)源于MSCs，而未分化的骨髓基質(zhì)細(xì)胞具有自我更新及向骨、肌肉、肌腱、脂肪分化的潛力。內(nèi)源性或外源性環(huán)境因素可以影響MSCs向成骨細(xì)胞轉(zhuǎn)化。內(nèi)、外微環(huán)境失調(diào)或受到其他刺激(如促腫瘤炎癥細(xì)胞因子)引起細(xì)胞增殖與分化失衡，最終導(dǎo)致惡性腫瘤的發(fā)生。

成骨細(xì)胞與骨肉瘤細(xì)胞不僅在細(xì)胞增生性、抗凋亡及其基因表達(dá)譜上有高度相似性，且二者都能表達(dá)堿性磷酸酶(ALP)、結(jié)締組織生長(zhǎng)因子(CTGF)。成骨細(xì)胞系、未分化或侵襲性較小的腫瘤細(xì)胞中存在細(xì)胞分化缺陷。研究發(fā)現(xiàn)，在高度侵襲性的OS細(xì)胞中，骨鈣素(OCN)、骨橋蛋白(OPN)表達(dá)量較低，但二者在成熟的成骨細(xì)胞中表達(dá)量較高[45]。OS細(xì)胞可以通過(guò)通過(guò)端粒的替代延長(zhǎng)(alternative lengthening of telomeres，ALT)抗衰老晚期成骨細(xì)胞,而成骨細(xì)胞則不具備這一能力。大多數(shù)終末分化的成骨細(xì)胞因復(fù)制次數(shù)增多而導(dǎo)致端?？s短，OS細(xì)胞通過(guò)ALT方式使其保持類干細(xì)胞狀態(tài)及應(yīng)對(duì)外源性刺激。

骨形成蛋白(BMPs)代表了一類對(duì)OS細(xì)胞刺激因子。一般認(rèn)為BMPs能夠促進(jìn)MSCs向成骨細(xì)胞系分化?，F(xiàn)有報(bào)道證實(shí)BMPs不僅能夠誘導(dǎo)OS細(xì)胞的分化，更能夠增強(qiáng)OS細(xì)胞侵襲性。這主要是因?yàn)檗D(zhuǎn)錄因子Rnux2的低表達(dá)。Runx2能能夠通過(guò)調(diào)節(jié)BMP活性來(lái)阻滯細(xì)胞周期及促進(jìn)細(xì)胞終末分化。然而Martin等[46]研究表明RUNX2基因的過(guò)表達(dá)與骨肉瘤患者預(yù)后呈負(fù)相關(guān)，提示RNUX2的表達(dá)對(duì)成骨細(xì)胞的調(diào)控有密切關(guān)聯(lián)。

BMPs是通過(guò)Wnt糖蛋白信號(hào)通路發(fā)揮作用。Wnt糖蛋白信號(hào)通路已經(jīng)被證實(shí)能夠發(fā)揮抑制成骨細(xì)胞分化的作用[47]。Wnt信號(hào)通路異常可通過(guò)典型與非典型的β-catenin通路致使細(xì)胞分化及遷移能力增加[48]。除BMPs、Runx2及Wnt外，又不斷發(fā)現(xiàn)可以促進(jìn)OS細(xì)胞分化的蛋白。這些蛋白包括核受體家族的超級(jí)蛋白PPARγ、視黃醇、雌激素等，研究證實(shí)上述蛋白可以抑制細(xì)胞增殖、提高OS細(xì)胞對(duì)凋亡易感性[49]。p21是一種促凋亡細(xì)胞周期調(diào)控因子，調(diào)控成骨細(xì)胞分化及凋亡，核受體激動(dòng)劑-1，25-二羥維生素D3(D3[1,25(OH) 2D3])，通過(guò)上調(diào)能夠p21表達(dá)水平[50]。總結(jié)上述研究不難發(fā)現(xiàn)細(xì)胞分化缺失在骨肉瘤發(fā)生過(guò)程中發(fā)揮關(guān)鍵作用。

4 小結(jié)

綜上所述，骨肉瘤發(fā)病機(jī)制的研究在分子生物學(xué)領(lǐng)域愈發(fā)廣泛和深入，使得未來(lái)對(duì)于骨肉瘤治療有更多的可能。隨著研究的深入，可以更好的理解不同信號(hào)通路與細(xì)胞分化途徑之間的聯(lián)系，也就為發(fā)現(xiàn)在骨肉瘤發(fā)生、發(fā)展中起關(guān)鍵作用的信號(hào)通路、分子提供了可能，進(jìn)而也就能針對(duì)這些信號(hào)通路、分子設(shè)計(jì)出更加高效低毒的抗腫瘤藥物，提高骨肉瘤患者生活質(zhì)量，改善預(yù)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

湖北省衛(wèi)生計(jì)生委西醫(yī)類一般項(xiàng)目（編號(hào)：WJ2015MB172）

杜遠(yuǎn)立。E-mail：Duyuanli2008@163.com