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        甲狀腺未分化癌的遺傳學(xué)改變研究進(jìn)展

        2017-06-06 18:11:43趙佳正
        中國(guó)當(dāng)代醫(yī)藥 2017年12期
        關(guān)鍵詞:分子機(jī)制基因

        趙佳正

        [摘要]甲狀腺未分化癌是一種惡性程度很高的腫瘤,區(qū)別于分化型甲狀腺癌,常規(guī)的手術(shù)、放療及化療治療效果較差。隨著甲狀腺未分化癌分子發(fā)病機(jī)制的不斷研究,許多遺傳學(xué)改變都被認(rèn)為參與了甲狀腺未分化癌發(fā)生、發(fā)展的過(guò)程,為甲狀腺未分化癌的分子靶向治療提供了新的可能。本文將介紹與甲狀腺未分化癌發(fā)病相關(guān)的遺傳學(xué)改變的研究進(jìn)展,主要包括RAS/RAF/MAPK/ERK信號(hào)通路和PI3K/Akt mTOR信號(hào)通路。

        [關(guān)鍵詞]甲狀腺未分化癌;分子機(jī)制;基因

        [中圖分類號(hào)] R736.1 [文獻(xiàn)標(biāo)識(shí)碼] A [文章編號(hào)] 1674-4721(2017)04(c)-0016-04

        [Abstract]As a highly malignant tumor,anaplastic thyroid carcinoma is different from differentiated thyroid cancer,conventional surgery,radiotherapy and chemotherapy can achieve poor results in the treatment of thyroid undifferentiated carcinoma.With the unceasing research on molecular pathogenesis of anaplastic thyroid carcinoma,many genetic changes are thought to be involved in the development process of anaplastic thyroid carcinoma and to provide a new possibility for molecular targeted treatment of thyroid undifferentiated carcinoma.In this paper,the research progress of the genetic changes related to the pathogenesis of anaplastic thyroid carcinoma is introduced,including RAS/RAF/MAPK/ERK signaling pathway and PI3K/Akt mTOR signaling pathway.

        [Key words]Anaplastic thyroid carcinoma;Molecular mechanism;Gene

        近年來(lái)甲狀腺癌的發(fā)病率不斷上升,已經(jīng)成為最常見(jiàn)的內(nèi)分泌腫瘤[1]。根據(jù)甲狀腺癌病理組織類型,可分為乳頭狀甲狀腺癌(papillary thyroid cancer,PTC)、濾泡狀甲狀腺癌(follicular thyroid cancer,F(xiàn)TC)、低分化型甲狀腺癌(poorly differentiated thyroid cancer,PDTC)和甲狀腺未分化癌(anaplastic thyroid carcinoma,ATC),其中PTC和FTC又被稱為分化型甲狀腺癌(differentiated thyroid cancer,DTC)。ATC是一種惡性程度很高的腫瘤,在所有甲狀腺癌中占2%~15%,導(dǎo)致了絕大多數(shù)的甲狀腺癌相關(guān)死亡,中位生存期為6個(gè)月,臨床表現(xiàn)為迅速增長(zhǎng)的頸部腫塊,常常伴隨壓迫癥狀[2-3]。ATC常具有高度侵襲性,容易發(fā)生腺體外侵犯及淋巴結(jié)轉(zhuǎn)移,60%的患者有遠(yuǎn)處轉(zhuǎn)移,ATC的TNM分期均為Ⅳ期[3]。在過(guò)去的幾十年中,ATC生存的改善微乎其微[4],也正因?yàn)槿绱?,?duì)ATC分子發(fā)病機(jī)制的研究就顯得尤為重要。研究人員試圖通過(guò)遺傳學(xué)改變的研究找到治療ATC的新途徑。

        甲狀腺癌惡性程度進(jìn)展被認(rèn)為是一個(gè)多步驟的腫瘤發(fā)生過(guò)程,甲狀腺濾泡細(xì)胞早期發(fā)生的RAS、BRAF導(dǎo)致分化型甲狀腺癌的發(fā)生,而p53基因失活突變導(dǎo)致了細(xì)胞進(jìn)一步失分化而出現(xiàn)甲狀腺低分化癌(PDTC)和ATC[5]。與ATC發(fā)生相關(guān)的基因組改變主要包括RAS/RAF/MAPK/ERK信號(hào)通路、PI3K/Akt mTOR信號(hào)通路[5-6],下面將按照遺傳學(xué)改變的類型(基因突變、基因重排和基因拷貝數(shù)增加)分類闡述。

        1基因突變

        1.1 Ras突變

        Ras家族包括K-ras、H-ras及N-ras,Ras位于RAF/MAPK及PI3K/Akt mTOR的上游,Ras突變會(huì)導(dǎo)致這兩條通路異?;罨痆7]。RAS突變常見(jiàn)于濾泡性甲狀腺癌,但在PTC和ATC中也有報(bào)道[8]。在對(duì)甲狀腺癌的組織病理研究中,發(fā)現(xiàn)高達(dá)60%的ATC出現(xiàn)Ras突變,而在PTC中突變率<15%,PDTC中突變率為30%~35%[9],可見(jiàn)Ras突變頻率與分化程度成負(fù)相關(guān)。在甲狀腺癌發(fā)展的過(guò)程中,RAS似乎是一個(gè)“早期”突變,RAS突變被認(rèn)為啟動(dòng)了DTC到ATC這個(gè)去分化過(guò)程,因?yàn)镽AS突變會(huì)使細(xì)胞發(fā)生基因和分子錯(cuò)排,例如導(dǎo)致染色體不穩(wěn)定[10]。

        1.2 BRAF突變

        RAF家族包括ARAF、BRAF和CRAF 3種亞型。BRAF是Raf絲氨酸/蘇氨酸激酶家族中的一員,是Ras的下游效應(yīng)器,在正常甲狀腺細(xì)胞增殖、凋亡及甲狀腺特異基因表達(dá)中起重要的調(diào)節(jié)作用[11]。研究顯示,大鼠甲狀腺細(xì)胞中BRAF基因突變及隨后的MAPK的活化能沉默鈉/碘協(xié)同轉(zhuǎn)運(yùn)體(sodium/iodide symporter,NIS)的表達(dá),而通過(guò)siRNA去除BRAF突變可以恢復(fù)甲狀腺特異性基因的表達(dá)[12],BRAFV600E突變被證實(shí)會(huì)阻礙NIS基因的表達(dá)以及NIS的膜定位,而通過(guò)抑制BRAF,可逆轉(zhuǎn)NIS轉(zhuǎn)錄抑制[12]。BRAFV600E突變可導(dǎo)致DTC細(xì)胞中甲狀腺特異蛋白表達(dá)下調(diào),促進(jìn)去分化,還與轉(zhuǎn)移和侵襲相關(guān)[13]?;贐RAF突變?cè)贒TC以及DTC轉(zhuǎn)化成ATC中發(fā)揮重要作用,BRAF突變成為治療ATC的研究靶點(diǎn)[14]。

        1.3 PI3K突變

        磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinage,PI3K)為脂激酶家族,參與細(xì)胞增殖、存活。磷脂酰肌醇3-激酶/蛋白激酶B/哺乳動(dòng)物雷帕霉素靶蛋白(phosphatidylinositol 3-kinage/protein kinase B/mammaliantarget of rapamycin,P13K/Akt mTOR)信號(hào)通路與ATC的發(fā)生、發(fā)展密切相關(guān)[15],其中的PI3K突變是最常見(jiàn)的突變,ATC中PI3K突變發(fā)生的頻率遠(yuǎn)高于PTC[7]。PI3K突變可通過(guò)抑制cAMP而降低NIS表達(dá),使得甲狀腺癌細(xì)胞向未分化方向發(fā)展,同時(shí)PI3K突變可上調(diào)下游的mTOR含量,mTOR可促進(jìn)細(xì)胞增殖、抑制細(xì)胞凋亡,mTOR又可以降低NIS表達(dá)[16]。

        1.4 p53突變

        p53是一種抑癌基因,編碼的蛋白質(zhì)分子量為53 kDa,是一種轉(zhuǎn)錄因子,p53抑癌基因在調(diào)節(jié)細(xì)胞周期和細(xì)胞凋亡中的起重要作用[17]。p53基因在DTC中突變頻率低而在ATC中突變頻率可高達(dá)95%,在并發(fā)PTC和ATC的病理組織中,可在ATC組織中檢測(cè)到p53突變,而在PTC中檢測(cè)不到[18]。有學(xué)者提出了“兩步機(jī)制”,甲狀腺癌中,在BRAF突變的細(xì)胞基礎(chǔ)上發(fā)生p53基因的突變,使得腫瘤失分化,p53突變的出現(xiàn)是一個(gè)晚期事件,其使得腫瘤轉(zhuǎn)化和去分化而變得更具侵略性[19-20]。目前,針對(duì)p53的靶向治療已成為研究熱點(diǎn)。

        1.5 β-catenin基因突變

        β-catenin是一種多功能蛋白分子,分布于細(xì)胞質(zhì)中,高達(dá)60%~65%的ATC中存在β-catenin突變[21]。在ATC中,β-catenin基因突變主要涉及Wnt/β-catenin通路以及與E-cadherin/β-catenin相關(guān)的細(xì)胞黏附系統(tǒng)。β-catenin在細(xì)胞增殖和細(xì)胞黏附中都發(fā)揮作用。Wnt/β-catenin通路中過(guò)度表達(dá)的β-catenin會(huì)進(jìn)入細(xì)胞核內(nèi),引起細(xì)胞持續(xù)增殖;E-cadherin/β-catenin的細(xì)胞黏附系統(tǒng)中β-catenin突變會(huì)使細(xì)胞間黏附力減弱,進(jìn)而增加腫瘤細(xì)胞的侵襲性[22]。

        1.6 Notch

        Notch受體(Notch1-4)及其配體不同情況下可調(diào)節(jié)細(xì)胞的增殖,遷移、黏附和分化[23]。Ferretti等[24]首次證實(shí),與正常甲狀腺組織相比,Notch在DTC中表達(dá)明顯降低,而在ATC中進(jìn)一步降低,Notch 1對(duì)細(xì)胞生長(zhǎng)和分化的影響是通過(guò)調(diào)控基因轉(zhuǎn)錄來(lái)實(shí)現(xiàn)。雖然在其他組織和癌癥中有許多研究,但Notch 1在甲狀腺癌中的作用最近才被探索。作為Notch 1下游效應(yīng)分子,Hes 1在甲狀腺細(xì)胞增殖和分化中起中心作用,在Hes 1(-/-)小鼠胚胎中,甲狀腺表面積減少了34%~65%,NIS蛋白減少69%[25]。

        1.7 NF-κB

        核因子κB(NF-κB)屬于轉(zhuǎn)錄因子家族,可被多種促炎細(xì)胞因子、化療藥物和電離輻射激活[26]。許多NF-κB靶基因是促生存基因,對(duì)癌細(xì)胞固有的化療和放射治療抵抗至關(guān)重要,體外和體內(nèi)各種腫瘤細(xì)胞包括甲狀腺癌在內(nèi)的研究中,通過(guò)抑制NF-κB活性會(huì)導(dǎo)致細(xì)胞凋亡或增強(qiáng)化療和放射治療的敏感性[27]。在PTC、FTC及ATC中均發(fā)現(xiàn)NF-κB被激活,因此,抑制NF-κB的活化被認(rèn)為可通過(guò)腫瘤細(xì)胞的內(nèi)在和外在機(jī)制加強(qiáng)化療和放射治療的作用[28]。

        2基因重排

        RET原癌基因位于染色體10q11.21,其包含了21個(gè)外顯子,編碼一跨膜的絡(luò)氨酸激酶受體,包含了1114個(gè)氨基酸[29]。目前文獻(xiàn)共報(bào)道了13種甲狀腺癌 RET/PTC基因重排,發(fā)生RET/PTC基因重排后會(huì)導(dǎo)致RET基因的持續(xù)活化,進(jìn)而活化下游的RAS基因,RET/PTC基因重排會(huì)導(dǎo)致染色體不穩(wěn)定,使細(xì)胞失分化[30]。另一個(gè)常見(jiàn)的易位是TRK-fused(TFG)和受體酪氨酸激酶NTRK 1,類似于RET的染色體重排,一些TFG的融合蛋白同樣會(huì)導(dǎo)致MAPK激酶過(guò)度激活[31]。

        3基因拷貝數(shù)增加

        受體酪氨酸激酶(receptor tyrosine kinase,RTK)是最大的一類酶聯(lián)受體,包括了50余種,而常見(jiàn)的表皮生長(zhǎng)因子受體(epidermal growth factor receptor,EGFR)、血小板生長(zhǎng)因子受體(platelet-derived growth factor receptor,PDGFR)、血管內(nèi)皮生長(zhǎng)因子受體(vascularendothelial growth factor receptor,VEGFR)等突變與多種腫瘤的發(fā)生相關(guān)[32]。在ATC中,RTK的突變并不常見(jiàn),但RTK基因拷貝數(shù)的增加較為常見(jiàn)。一項(xiàng)研究發(fā)現(xiàn),ATC中發(fā)生相應(yīng)基因拷貝數(shù)增加的頻率分別為:EGFR 46.3%,PDGFR 23.9%,VEGFR 45.5%,而PIK3C基因拷貝數(shù)增加的頻率為38.3%[33]。

        總之,ATC惡性程度高,預(yù)后差,至今仍未找到較好的治療手段,傳統(tǒng)的手術(shù)、化療、放療效果都不理想,而分子機(jī)制的研究發(fā)現(xiàn),ATC中存在多種基因突變及基因異常擴(kuò)增,這些分子機(jī)制的研究或許能為該病的治療提供新的思路。

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        (收稿日期:2017-03-14 本文編輯:祁海文)

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