常棟，劉享享，劉睿，孫建偉

綜 述

FSCN1在乳腺癌發(fā)生發(fā)展中的作用及其調(diào)控機(jī)制

常棟1，劉享享1，劉睿2，孫建偉1

1. 云南大學(xué)生命科學(xué)學(xué)院，生命科學(xué)研究中心，昆明 650504 2. 昆明醫(yī)科大學(xué)第三附屬醫(yī)院乳腺外科，昆明 650118

FSCN1是一種肌動蛋白結(jié)合蛋白，能夠?qū)⒓拥鞍捉z集成一束。FSCN1在幾乎所有的轉(zhuǎn)移性腫瘤中高表達(dá)，并與大部分腫瘤的不良預(yù)后密切相關(guān)。在基底樣和三陰性乳腺癌中高度表達(dá)。近年來關(guān)于FSCN1的報道愈發(fā)頻繁，隨著深入研究發(fā)現(xiàn)，F(xiàn)SCN1除了促進(jìn)癌細(xì)胞的遷移、侵襲和轉(zhuǎn)移定植，維持癌細(xì)胞自我更新和增強(qiáng)耐藥性，還具有調(diào)控癌細(xì)胞的糖脂代謝及線粒體重塑等功能。本文從FSCN1的結(jié)構(gòu)和調(diào)節(jié)形式，促進(jìn)乳腺癌發(fā)生和轉(zhuǎn)移的分子機(jī)制，以及其在乳腺癌中的作用及功能展開介紹，最后對FSCN1在臨床上的價值進(jìn)行了總結(jié)，為FSCN1在乳腺癌領(lǐng)域的研究提供重要的借鑒和參考。

FSCN1；肌動蛋白集束；乳腺癌；腫瘤發(fā)生；腫瘤進(jìn)展

據(jù)國際癌癥研究機(jī)構(gòu)2021年發(fā)布的癌癥統(tǒng)計數(shù)據(jù)分析，乳腺癌目前在全球的癌癥發(fā)病率中高居首位，是危害女性健康的主要疾病之一[1]。盡管對于乳腺癌(主要是激素受體陽性和人表皮生長因子受體陽性的乳腺癌)的治療已取得一定進(jìn)展，但仍有相當(dāng)比例的乳腺癌患者復(fù)發(fā)[2]并且經(jīng)歷轉(zhuǎn)移[3]，尤其是惡性程度最高的三陰性乳腺癌(triple nega-tive breast cancer，TNBC)患者。因此，尋找乳腺癌的新型標(biāo)志物和有效的治療靶點，對改善患者的生存質(zhì)量尤為關(guān)鍵。

腫瘤轉(zhuǎn)移是一個復(fù)雜、多步驟的過程。原發(fā)性腫瘤經(jīng)過上皮–間質(zhì)轉(zhuǎn)化(epithelial-mesenchymal transition, EMT)獲得向周圍組織和循環(huán)系統(tǒng)的遷移和侵襲能力，EMT的激活導(dǎo)致癌細(xì)胞間連接破壞、基質(zhì)重組和基底膜的降解，并經(jīng)歷細(xì)胞骨架的廣泛重塑等一系列的變化[4]。具有EMT特征的癌癥干細(xì)胞(cancer stem cells，CSCs)內(nèi)滲到附近血管或淋巴，通過循環(huán)系統(tǒng)散播到遠(yuǎn)處組織的微血管，少數(shù)“幸運(yùn)”的癌細(xì)胞在適宜的條件下從微血管壁處逃逸并成功定植，形成轉(zhuǎn)移性腫瘤[5]。乳腺癌細(xì)胞更容易向骨、肝臟、肺、腦等部位轉(zhuǎn)移[6]，但不同乳腺癌亞型的轉(zhuǎn)移行為也各有特點[3]。

肌動蛋白作為細(xì)胞骨架蛋白，可以為細(xì)胞提供內(nèi)部的機(jī)械支撐，驅(qū)動細(xì)胞運(yùn)動并控制胞內(nèi)物質(zhì)運(yùn)動的軌跡，對大多數(shù)細(xì)胞的生存至關(guān)重要[7]。FSCN(fascin actin-bundling protein)最開始在海膽提取物中被鑒定為絲狀肌動蛋白(F-actin)集束蛋白[8]，與在鱟()精子中發(fā)現(xiàn)的細(xì)絲束成分中大小為55 kDa的蛋白同源[9]。作為一種關(guān)鍵的特異性肌動蛋白交聯(lián)劑，F(xiàn)SCN可以將肌動蛋白絲捆綁成平行的一束，直接參與細(xì)胞運(yùn)動和遷移、細(xì)胞–基質(zhì)黏附、偽足形成等過程[10]。家族有三個亞型：表達(dá)于神經(jīng)細(xì)胞、內(nèi)皮細(xì)胞、間充質(zhì)細(xì)胞和樹突狀細(xì)胞，而在正常的上皮細(xì)胞中不表達(dá)或低水平表達(dá)[11]，并在幾乎所有類型的轉(zhuǎn)移性癌癥中高表達(dá)[12]；在視網(wǎng)膜和耳中特異性表達(dá)，小鼠中的無義突變會導(dǎo)致進(jìn)行性聽力損失和視網(wǎng)膜變性[13]；在睪丸及精子頭部特異性表達(dá)[14]。近年來，有關(guān)FSCN1在乳腺癌發(fā)生發(fā)展及轉(zhuǎn)移中的作用機(jī)制研究越來越多。本實驗室及其他實驗室的研究表明，高表達(dá)介導(dǎo)乳腺癌細(xì)胞的遷移、侵襲、轉(zhuǎn)移定植和化療耐藥以及自我更新[15～23]，并與乳腺癌的不良預(yù)后密切相關(guān)，因此，F(xiàn)SCN1可作為某些類型乳腺癌的標(biāo)志物和潛在的治療靶點[24～32]。本文將主要圍繞FSCN1的結(jié)構(gòu)和調(diào)節(jié)形式，其促進(jìn)乳腺癌發(fā)生和轉(zhuǎn)移的分子調(diào)控機(jī)制、在乳腺癌中行使的功能展開綜述，最后對FSCN1在臨床上的價值進(jìn)行了探討和展望。

1 FSCN1的結(jié)構(gòu)

是定位在人7號染色體短臂2區(qū)2帶(7p22)、由5個外顯子組成、大小為13,840 bp的高度保守DNA序列(圖1A)。第一個外顯子包括5′非翻譯區(qū)(5′ untranslated region，5′UTR)和大約一半的編碼序列，由9.5 kb長的內(nèi)含子1分隔；下游短外顯子2～4在0.8 kb范圍內(nèi)間隔排列，總共編碼30%的開放閱讀框；外顯子5位于下游1.2 kb處，包含剩余的編碼部分和3′非翻譯區(qū)(3′UTR)。

FSCN1是一種由493個氨基酸殘基組成的、分子量大小為55 kDa的球狀蛋白(圖1B)。FSCN1蛋白在進(jìn)化上是高度保守的，表明FSCN1可能行使某些基本的生物學(xué)功能，例如肌動蛋白集束活性的功能[33]。其493個殘基通過一系列相互作用構(gòu)成四個串聯(lián)的β-三葉結(jié)構(gòu)域(β-Trefoli)，N端和C端分別位于β-Trefoli1和β-Trefoli4上[34]。FSCN1具有三個不同的結(jié)合肌動蛋白的表面區(qū)域，其中兩個較大的肌動蛋白結(jié)合區(qū)域 (actin-bindingsite, ABS)位于β-Trefoli1和β-Trefoli4上以及β-Trefoli1和β-Trefoli2的裂縫中[35]，而第三個較小的區(qū)域(ABS3)位于β-Trefoli3上[36]。對FSCN1在絲狀偽足中捆綁肌動蛋白的低溫電子顯微鏡分析表明，ABS1和ABS2與一個肌動蛋白絲結(jié)合，ABS3結(jié)合第二個肌動蛋白絲[35,37]。

圖1 FSCN1的結(jié)構(gòu)

A：FSCN1的基因結(jié)構(gòu)，框內(nèi)是參與轉(zhuǎn)錄后調(diào)控的microRNA(miRNA)。B：FSCN1蛋白的三維結(jié)構(gòu)，ABS和β-Trefoli分別代表FSCN1的肌動蛋白結(jié)合區(qū)域和結(jié)構(gòu)域，內(nèi)側(cè)標(biāo)注四個氨基酸殘基是FSCN1翻譯后修飾的主要位點。

2 FSCN1在乳腺癌中的調(diào)控

2.1 FSCN1的轉(zhuǎn)錄調(diào)控

的核心啟動子含有一個TATA盒和一個GC框，以及cAMP反應(yīng)元件結(jié)合蛋白/激活蛋白1(cyclic AMP response element binding protein, CERB/AP-1)復(fù)合位點等其他幾個轉(zhuǎn)錄因子結(jié)合位點[38]，在乳腺癌細(xì)胞中，信號轉(zhuǎn)導(dǎo)和轉(zhuǎn)錄激活因子3 (signaltransducerandactivatoroftranscription3, STAT3)、核因子κB(nuclear factor kappa B, NF-κB) 等轉(zhuǎn)錄因子可以通過結(jié)合到的啟動子區(qū)調(diào)控的表達(dá)(圖2)。

2.1.1 JAK-STAT通路

炎癥是促進(jìn)腫瘤發(fā)生發(fā)展的重要因素。癌細(xì)胞通過與細(xì)胞間質(zhì)相互作用、招募免疫細(xì)胞等方式來制造炎性腫瘤微環(huán)境，從而促進(jìn)自身的增殖和轉(zhuǎn)移[39]。作為經(jīng)典的炎癥通路，炎性因子通過JAK(Januskinase)-STAT途徑影響腫瘤發(fā)生及進(jìn)展。在乳腺癌中，STAT3作為轉(zhuǎn)錄因子與的啟動子特異性結(jié)合來調(diào)控的表達(dá)。

在乳腺癌細(xì)胞(4T1、MDA-MB-231)中，STAT3作為轉(zhuǎn)錄因子通過響應(yīng)白介素-6(interleukin6，IL-6)或抑瘤素M (oncostatin M，OSM)與的啟動子特異性結(jié)合來誘導(dǎo)的表達(dá)，并且NF-κB也以STAT3依賴性方式被募集到啟動子處[40]。在MDA-MB-231細(xì)胞中，經(jīng)過IL-6或腫瘤壞死因子-α (tumor necrosis factor α, TNF-α)等炎性因子的刺激，STAT3和NF-κB(P50、P65)在細(xì)胞核中形成蛋白復(fù)合物，并與啟動子的160bp保守區(qū)域上的STAT和NF-κB共同結(jié)合位點GGGGAA重疊序列結(jié)合以誘導(dǎo)其表達(dá)[41]，這說明STAT3/NF-κB復(fù)合物的形成有利于乳腺癌細(xì)胞中的表達(dá)。

最近的研究發(fā)現(xiàn)一些化合物可以特異性抑制JAK-STAT通路來下調(diào)的表達(dá)。例如，從黃孢屬植物中鑒定出的氯丹型二萜Crispene E[42]，可以與STAT3的SH2結(jié)構(gòu)域(src homology 2 domain)相互作用抑制STAT3的二聚化，進(jìn)而下調(diào)MDA- MB-231細(xì)胞中的水平。從南海的白鏈霉菌SCSIOZH16中分離出來的新型化合物島霉素 C (Ilamycin C)[43]，能夠抑制IL-6誘導(dǎo)的JAK2或STAT3的磷酸化來降低STAT3的磷酸化水平，進(jìn)而抑制的表達(dá)和TNBC細(xì)胞的遷移和侵襲。

2.1.2 NF-κB通路

NF-κB被認(rèn)為是慢性炎癥引起某些腫瘤進(jìn)展的關(guān)鍵因子，在腫瘤中NF-κB發(fā)揮調(diào)控癌細(xì)胞的增殖和存活、EMT以及血管生成等多種作用[44]。在乳腺癌中NF-κB也是調(diào)控表達(dá)的關(guān)鍵轉(zhuǎn)錄因子。除了與STAT3協(xié)同作用促進(jìn)的上調(diào)外，鞘氨醇(sphingosine, Sph)被鞘氨醇激酶1 (sphingosine kinase1, SPHK1)磷酸化后生成1-磷酸鞘氨醇(sphingosine-1-phosphate, S1P)，隨后與腫瘤壞死因子受體相關(guān)因子2 (TNF receptor associatedfactor2, TRAF2)特異性結(jié)合并激活其E3泛素連接酶活性從而啟動經(jīng)典的NF-κB信號通路[45]，也上調(diào)了的表達(dá)。此外，亮氨酸氨肽酶3 (leucineaminope-ptidase3, LAP3)通過阻斷p38-Hsp27通路促進(jìn)NF-κB的激活，進(jìn)而促進(jìn)的上調(diào)[46]，因此，來自天然海產(chǎn)品的LAP3抑制劑可高效地抑制該通路引起的效應(yīng)[47]。

圖2 調(diào)控FSCN1表達(dá)的相關(guān)信號通路

2.1.3 TGFβ-SMAD通路

入組標(biāo)準(zhǔn)：1）留守學(xué)生組 留守年限＞1年的留守學(xué)生進(jìn)入本組；2）非留守學(xué)生組 在進(jìn)入留守學(xué)生組的學(xué)生同一班級按1：1配對，隨機(jī)抽取性別、年齡相同的非留守學(xué)生進(jìn)入本組。

轉(zhuǎn)化生長因子β (transforming growth factor beta，TGFβ)在發(fā)育、組織動態(tài)平衡和再生過程中起調(diào)節(jié)細(xì)胞命運(yùn)的作用，是免疫功能障礙和各種先天性疾病、纖維化疾病的主要參與者[48]。作為腫瘤微環(huán)境中免疫抑制的中心，TGFβ信號的異常是炎癥發(fā)生的基礎(chǔ)，并促進(jìn)腫瘤的進(jìn)展。在乳腺癌中，TGFβ信號通路也調(diào)控的表達(dá)。

TGFβ通過經(jīng)典的TGFβ-SMAD (mothersagainstdecapentaplegichomolog)途徑誘導(dǎo)梭形腫瘤細(xì)胞中的表達(dá)，并且FSCN1在TGFβ促進(jìn)的腫瘤轉(zhuǎn)移中發(fā)揮核心作用[23]。本實驗室的研究表明TGFβ通過激活SMAD3/SMAD4特異性地誘導(dǎo)的表達(dá)，在基底樣乳腺癌細(xì)胞中，TGFβ激活SMAD3后，促進(jìn)SMAD4直接與啟動子的CAGAC結(jié)合位點相互作用從而促進(jìn)的表達(dá)，但是異位表達(dá)GATA結(jié)合蛋白3(GATAbindingprotein3, GATA3)后抑制了TGFβ-SMAD3/4介導(dǎo)的的轉(zhuǎn)錄[49]，結(jié)果證明GATA3抑制了SMAD3/4和啟動子區(qū)結(jié)合進(jìn)而抑制了的表達(dá)。

2.1.4 EGF/EGFR通路

表皮生長因子受體(epidermal growth factor receptor, EGFR)是一種典型的受體酪氨酸激酶，在增殖和遷移、調(diào)節(jié)細(xì)胞內(nèi)轉(zhuǎn)運(yùn)等基本細(xì)胞功能中起著關(guān)鍵作用；在腫瘤發(fā)生中，EGFR與有絲分裂信號和轉(zhuǎn)運(yùn)失調(diào)有密切關(guān)聯(lián)[50]，同時EGFR介導(dǎo)的通路或信號軸對乳腺癌中的表達(dá)調(diào)控起到重要的作用。

在表皮生長因子(epidermalgrowthfactor, EGF)刺激后的TNBC細(xì)胞中，的mRNA和蛋白質(zhì)表達(dá)水平均顯著增加，隨后使用絲裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)特異性抑制劑U0126可降低的mRNA和蛋白表達(dá)水平，并且可阻斷EGF對表達(dá)的促進(jìn)作用[51]，這說明部分TNBC細(xì)胞系通過EGFR-MAPK通路介導(dǎo)FSCN1的上調(diào)從而促進(jìn)TNBC的侵襲能力。

EGFR還介導(dǎo)Rab25對的調(diào)控作用：轉(zhuǎn)運(yùn)蛋白Rab25 (ras-related protein 25)將β1整合素(integrinsubunitbeta1, ITGB1)從內(nèi)體運(yùn)輸?shù)劫|(zhì)膜，二者協(xié)調(diào)激活EGFR，隨后引起 A型血管表皮生長因子(vascularendothelialgrowthfactor A, VEGF-A)和Snail(zincfinger proteinSNAI1)的上調(diào)[52]。作為EMT過程的核心轉(zhuǎn)錄因子之一，Snail與啟動子上的特定位點結(jié)合，最終引起的上調(diào)，進(jìn)而促進(jìn)乳腺癌的侵襲和轉(zhuǎn)移。

作為EGF超家族中的一員，TGFα也可能通過EGFR介導(dǎo)的表達(dá)：有報道稱，TGFα消除了糖皮質(zhì)激素對緊密連接形成的刺激，并通過Ras(ratsarcoma)蛋白依賴性途徑逆轉(zhuǎn)大鼠乳腺上皮腫瘤細(xì)胞中類固醇誘導(dǎo)的的下調(diào)[53]。

2.1.5 Wnt/β-catenin通路

Wnt (wingless-typeMMTVintegrationsitefamily)/β-連環(huán)蛋白(β-catenin)通路作為發(fā)育及腫瘤發(fā)生的主要調(diào)節(jié)途徑，在調(diào)控腫瘤干細(xì)胞活性方面起重要作用[54]。由于癌細(xì)胞的干性特征，因此經(jīng)常發(fā)現(xiàn)Wnt信號途徑的突變，乳腺癌中異?；钴S的Wnt信號下游轉(zhuǎn)錄因子也導(dǎo)致了的過表達(dá)。

佛波酯蛋白激酶C激活劑(tissue plasminogen activator, TPA)在乳腺癌細(xì)胞(MCF-7)中通過蛋白激酶C(protein kinaseC, PKC)間接激活糖原合成酶激酶3β(glycogen synthase kinase 3 beta，GSK3β)以及上調(diào)Wnt1表達(dá)從而誘導(dǎo)細(xì)胞遷移[55]，伴隨著Wnt信號通路的開啟表達(dá)也相應(yīng)的上調(diào)，二十二碳六烯酸(docosahexaenoicacid, DHA)通過減弱PKC和Wnt1介導(dǎo)的的表達(dá)而有效地抑制TPA誘導(dǎo)的細(xì)胞遷移。此外，表皮生長因子受體2(erb-B2 receptor tyrosine kinase 2, ERBB2)過表達(dá)可能通過促進(jìn)Wnt/β-catenin信號通路來增強(qiáng)的轉(zhuǎn)錄活性，在此過程中，NF-κB也有一定程度的上調(diào)[56]。還有報道稱沙棗提取物抑制ERBB2表達(dá)和β-catenin的磷酸化，這在一定程度上抑制了的過表達(dá)[57]。

2.1.6 RhoA-ROCK1軸

定位在細(xì)胞-細(xì)胞外基質(zhì)粘附位點的Ras抑制蛋白1(ras suppressor protein 1，RSU-1)在乳腺癌細(xì)胞中以生長分化因子15(growthdifferentiationfactor15, GDF-15)依賴的方式通過RhoA(ras homolog family member A)-ROCK1(rho associated coiled-coil contai-ning protein kinase 1)-軸促進(jìn)表達(dá)[58]，并且RSU-1可能通過GDF-15將Ras信號通路與肌動蛋白細(xì)胞骨架調(diào)節(jié)聯(lián)系起來，但具體的機(jī)制仍需進(jìn)一步探究。

2.2 FSCN1的轉(zhuǎn)錄后調(diào)控

在乳腺癌中，miRNA參與的轉(zhuǎn)錄后調(diào)控(圖1A)。譬如miR-133a、miR-145、miR488等miRNA與mRNA的3′UTR結(jié)合抑制其轉(zhuǎn)錄活性或使其mRNA降解[59-61]，miR-30a間接調(diào)控的轉(zhuǎn)錄活性[62]，X-連鎖凋亡蛋白抑制因子(X-linked inhibitor of apoptosis, XIAP)的3′UTR可以作為內(nèi)源競爭RNA(competingendogenousRNA, ceRNA)競爭性結(jié)合miR-29a-5p，從而將的mRNA從miR-29a-5p的抑制中拯救出來[63]。

2.3 FSCN1的翻譯后修飾調(diào)控

在蛋白水平上，磷酸化是FSCN1最早被發(fā)現(xiàn)的翻譯后修飾的方式，也是調(diào)控FSCN1最主要的方式。Yamakita和Ono等[64,65]發(fā)現(xiàn)PKC在體外能夠磷酸化FSCN1的Ser39位點，并且在磷酸化后FSCN1與肌動蛋白結(jié)合的能力大大降低，說明Ser39位點磷酸化可以顯著抑制FSCN1的肌動蛋白集束活性。Zeng等[66]將Ser39和附近的Ser38及與這兩個氨基酸殘基具有偽二重對稱性的Tyr23和Ser274去磷酸化突變后發(fā)現(xiàn)，食管鱗癌細(xì)胞(KYSE-150)的增殖、遷移和絲狀偽足的形成能力均明顯增強(qiáng)，并且Ser38和Ser39殘基的雙重去磷酸化突變能最大限度地促進(jìn)食管鱗狀細(xì)胞癌(esophagealsquamouscellcarcinoma, ESCC)細(xì)胞的增殖、遷移和絲足的形成；Villari等[67]證明Ser274是FSCN1介導(dǎo)微管結(jié)合的關(guān)鍵殘基，該殘基的去磷酸化突變導(dǎo)致FSCN1與微管的高度穩(wěn)定結(jié)合。定點去磷酸化突變實驗說明FSCN1中可能還存在其他潛在的磷酸化位點，并且這些磷酸化位點會聯(lián)合調(diào)控細(xì)胞的行為。關(guān)于FSCN1磷酸化的修飾機(jī)制仍有待進(jìn)一步的探討。Cheng等[68]最近發(fā)現(xiàn)FSCN1在人胚胎腎細(xì)胞(HEK-293T)和食管鱗癌細(xì)胞(KYSE140)中與乙酰基轉(zhuǎn)移酶P300/CBP相關(guān)因子(P300/CBP associated factor，PCAF)共定位，并證明FSCN1與PCAF直接相互作用，并被PCAF在保守位點Lys471處乙?；SCN1的Lys471乙?；軌蝻@著抑制體外某些食管癌細(xì)胞遷移和小鼠體內(nèi)的腫瘤轉(zhuǎn)移，并且在臨床上ESCC組織中高水平的FSCN1乙?；cESCC患者的總生存期延長和無病生存期密切相關(guān)。Lin等[69]揭示了E3泛素連接酶Smurf1 (SMAD specific E3 ubiquitin protein ligase 1)直接催化FSCN1行使集束功能所必需的氨基酸殘基(主要是Lys247和Lys250)的單泛素化，Lys247和Lys250單泛素化可能會引入空間位阻從而減弱FSCN1與肌動蛋白相互作用，進(jìn)而抑制了結(jié)直腸癌上皮細(xì)胞(DLD-1)的體外遷移。

3 FSCN1在乳腺癌中的功能

3.1 調(diào)控遷移、侵襲和轉(zhuǎn)移

EMT是原發(fā)腫瘤細(xì)胞獲得轉(zhuǎn)移能力的核心步驟之一。細(xì)胞骨架的廣泛重塑、細(xì)胞間連接破壞、細(xì)胞外基質(zhì)重組等一系列深刻的變化使癌細(xì)胞獲得更強(qiáng)的運(yùn)動能力，從而容易向周圍組織和循環(huán)系統(tǒng)侵襲和遷移[4]。作為一種主要的肌動蛋白集束蛋白，F(xiàn)SCN1在乳腺癌進(jìn)展中行使了自身的保守性功能，同樣也是最重要的功能：促進(jìn)乳腺癌細(xì)胞的遷移、侵襲和轉(zhuǎn)移。

通過對BALB/c鼠的尾靜脈注射4T1細(xì)胞，在一段時間后用克隆形成實驗檢測肺轉(zhuǎn)移4T1細(xì)胞的數(shù)量發(fā)現(xiàn)，相較于對照組而言，敲降組的細(xì)胞轉(zhuǎn)移數(shù)量更少[16,20]。將攜帶熒光素酶的MDA-MB-231細(xì)胞通過尾靜脈注射到一種免疫缺陷鼠(NOD-SCID鼠)中，在40天內(nèi)通過活體成像觀察不同小鼠的肺轉(zhuǎn)移信號強(qiáng)度發(fā)現(xiàn)，與FSCN1敲降組小鼠相比，對照組的肺轉(zhuǎn)移信號明顯較強(qiáng)，尤其在40天時[16]。一些乳腺癌細(xì)胞系的遷移和侵襲試驗也是過表達(dá)促進(jìn)乳腺癌細(xì)胞遷移和侵襲的佐證[23,45,47,70]。這些證據(jù)都表明了過表達(dá)增強(qiáng)了不同類型乳腺癌細(xì)胞的轉(zhuǎn)移能力，并且FSCN1能與其他肌動蛋白相關(guān)蛋白相互協(xié)助以進(jìn)一步的促進(jìn)乳腺癌細(xì)胞的運(yùn)動[17]。但有報道稱高表達(dá)促進(jìn)MDA-MB-231細(xì)胞的轉(zhuǎn)移與其肌動蛋白捆綁活性無關(guān)[71]，這與大多數(shù)證據(jù)相矛盾，并且只突變Ser39這一肌動蛋白結(jié)合位點不足夠有說服力。當(dāng)然FSCN1也可能通過獨立于肌動蛋白集束功能的其他功能促進(jìn)腫瘤細(xì)胞轉(zhuǎn)移，這需要更進(jìn)一步的探索。

3.2 維持癌細(xì)胞干性和化療耐藥

大鼠白細(xì)胞分化抗原44(CD44)high、大鼠白細(xì)胞分化抗原24(CD24)low[72]及乙醛脫氫酶(aldehydedehydrogenase, ALDH)high[73]經(jīng)常作為鑒定乳腺癌干細(xì)胞的標(biāo)記物。在MDA-MB-231細(xì)胞中將敲降后，調(diào)節(jié)胚胎干細(xì)胞多能性的SRY-盒轉(zhuǎn)錄因子(SRY-box transcription factor 2, Sox2)等水平下調(diào)，乳腺癌中調(diào)節(jié)細(xì)胞自我更新的Notch通路及其下游靶標(biāo)也有明顯的下調(diào)[19]，F(xiàn)SCN1陽性的乳腺癌細(xì)胞集落形成能力更強(qiáng)，在裸鼠中皮下成瘤的體積更大，并且FSCN1與CD44high/CD24low或ALDHhigh干細(xì)胞標(biāo)志物的表達(dá)無關(guān)，這揭示了FSCN1通過激活Notch通路維持癌癥干細(xì)胞的自我更新能力。耐藥性是腫瘤干細(xì)胞的關(guān)鍵特征之一，將敲降和正常的MDA-MB-231細(xì)胞注射到裸鼠體內(nèi)后化療三個周期后，相對于對照組而言，敲降組的腫瘤體積要小得多。從分子層面來看，F(xiàn)SCN1在部分乳腺癌細(xì)胞中通過介導(dǎo)粘著斑激酶(focaladhesionkinase, FAK)的磷酸化激活PI3K(Phosphoinositide 3-kinase)-Akt (AKTserine/threonine kinase)[21]和β-catenin[18]信號級聯(lián)參與化療耐藥。以上說明FSCN1可能主要通過胚胎信號通路[74]參與乳腺癌細(xì)胞的干性維持和化療耐藥。

3.3 癌細(xì)胞增殖和腫瘤生長

有報道稱FSCN1在乳腺癌細(xì)胞(MDA-MB-435和MDA-MB-231)中異位表達(dá)增強(qiáng)了細(xì)胞的增殖能力[22]，并且在膽管癌、黑色素瘤及某些肺癌細(xì)胞中[75-77]FSCN1也具有調(diào)控細(xì)胞增殖的作用。Chen等[16]將4T1細(xì)胞的敲降后于完全培養(yǎng)基中培養(yǎng)，發(fā)現(xiàn)其生長速度與對照組相當(dāng)，這說明在體外4T1的增殖似乎與FSCN1無關(guān)。Hayashi、Xu等[78,79]在肝細(xì)胞癌和胰腺癌中將敲除或異位表達(dá)后對細(xì)胞的增殖幾乎沒有影響。當(dāng)然，鑒于不同腫瘤細(xì)胞系間的異質(zhì)性，在不同的癌癥類型及同種類型的不同細(xì)胞系中FSCN1表達(dá)與細(xì)胞增殖的關(guān)系也不盡相同，F(xiàn)SCN1與癌細(xì)胞增殖的關(guān)系仍亟待未來進(jìn)一步的探索。

4 FSCN1在臨床上的價值

針對激素受體陽性和人表皮生長因子受體陽性乳腺癌患者已有相對成熟的治療體系，但對轉(zhuǎn)移后的乳腺癌患者的治療仍不容樂觀[2]。TNBC作為乳腺癌中惡性程度最高的類型，發(fā)病率占乳腺癌的15%，但目前對其具體的分子病理學(xué)及生理學(xué)細(xì)節(jié)仍然知之甚少，患者在確診后3～5年的生存期急劇下降，并且近二十年沒有一種新的治療方法通過臨床三期試驗評估，傳統(tǒng)化療仍是臨床實踐中治療TNBC的唯一有效的手段[80]。因此，尋找合適的生物標(biāo)志物來改善乳腺癌診斷、預(yù)后和治療監(jiān)測已成為亟待解決的問題。

通過免疫組化(immunohistochemistry, IHC)及單核苷酸多態(tài)性(single nucleotide polymorphism, SNP)基因分型分析了FSCN1在臨床樣本中作為預(yù)測不良預(yù)后和腫瘤診斷標(biāo)記物的價值(表1)，同時結(jié)合其在腫瘤細(xì)胞中高表達(dá)的特點[81]，以及FSCN1在乳腺癌發(fā)生發(fā)展中的重要作用，初步說明FSCN1可作為一種有潛力的蛋白生物標(biāo)志物，以用于乳腺癌的風(fēng)險評估、診斷、預(yù)后，并用于預(yù)測治療效果和復(fù)發(fā)情況。已有證據(jù)表明，針對FSCN1的小分子抑制劑能夠有效的阻斷FSCN1引起的癌細(xì)胞遷移、侵襲和轉(zhuǎn)移(表2)。例如米格拉他汀類似物，作為一種肌動蛋白抑制劑，可以廣泛并有效的降低乳腺癌細(xì)胞的遷移能力，其通過占據(jù)FSCN1的肌動蛋白結(jié)合位點來抑制FSCN1的集束活性[16]。在小鼠模型中，米格拉他汀類似物G2的使用使MDA-MB-231細(xì)胞的肺定植減少了80%以上，同時也減少了4T1細(xì)胞的肺定植[16]，并且注射G2超2個月后小鼠也沒有體重減輕、嗜睡或其他明顯的毒性反應(yīng)[20]。其他的一些小分子化合物，如LAP3抑制劑[47]、Ilamycin C[43]、Crispene E[42]也具有抑制FSCN1依賴性的腫瘤遷移、侵襲和轉(zhuǎn)移的功能，這些小分子化合物為靶向FSCN1抗腫瘤轉(zhuǎn)移療法提供了廣闊的前景。

表1 FSCN1在臨床中的潛在價值

5 結(jié)語與展望

FSCN1作為一種重要的肌動蛋白集束蛋白，直接參與細(xì)胞運(yùn)動和遷移等過程[10]，并促進(jìn)了大多數(shù)類型癌癥的發(fā)生發(fā)展[12]。在乳腺癌中，JAK-STAT、NF-κB、TGFβ-Smad、Wnt/β-catenin等通路都能不同程度的上調(diào)的表達(dá)，的過表達(dá)會促進(jìn)乳腺癌細(xì)胞遷移和侵襲能力，有利于乳腺癌的遠(yuǎn)端轉(zhuǎn)移和定植，并賦予乳腺癌細(xì)胞維持干性和化療耐藥的能力。最近有研究表明FSCN1增強(qiáng)了鐵死亡誘導(dǎo)劑愛拉斯汀(Erastin)誘導(dǎo)的MDA-MB-231細(xì)胞鐵死亡的易感性[90]，這可能會為TNBC患者提供一個有潛力的治療方向。FSCN1與腫瘤細(xì)胞的代謝也存在密切聯(lián)系，此前本實驗室證明了FSCN1介導(dǎo)線粒體重塑及維持線粒體DNA穩(wěn)定來促進(jìn)線粒體氧化磷酸化[91]；在結(jié)直腸癌中，的敲除會導(dǎo)致編碼脂肪酸合成關(guān)鍵酶的脂肪酸合酶(fattyacidsynthase, FASN)和硬脂酰–輔酶A去飽和酶(stearoyl-CoAdesaturase，SCD)基因表達(dá)下調(diào)[92]；在非小細(xì)胞肺癌和前列腺癌中，F(xiàn)SCN1通過激活YAP1(yes1associated protein 1)-TEAD(TEA domain transcription factor)軸來促進(jìn)糖酵解[93,94]。另外有研究表明FSCN1通過增強(qiáng)YAP1的機(jī)械轉(zhuǎn)導(dǎo)能力以促進(jìn)膽管癌的發(fā)展[95]，綜合基因組學(xué)分析也證明在胃癌中FSCN1與TEAD4存在密切聯(lián)系[96]，以上研究表明FSCN1通過Hippo通路促進(jìn)腫瘤發(fā)生發(fā)展。另外，F(xiàn)SCN1還具有介導(dǎo)機(jī)械轉(zhuǎn)導(dǎo)、調(diào)節(jié)核仁形態(tài)和染色質(zhì)修飾的功能[81]，最新的研究表明，F(xiàn)SCN1能夠動態(tài)的進(jìn)出細(xì)胞核，其進(jìn)入核內(nèi)會與組蛋白H3直接結(jié)合，并促進(jìn)核F-actin的集束，以及促進(jìn)癌細(xì)胞DNA損傷后的DNA損傷應(yīng)答[97]。這些研究結(jié)果說明FSCN1在腫瘤發(fā)生及惡化中具有復(fù)雜而重要的作用，這些作用都依賴于FSCN1的肌動蛋白集束活性，至于FSCN1是否存在獨立于肌動蛋白集束活性的功能，仍需要進(jìn)一步的深入研究。

目前大量的研究表明的高表達(dá)水平與乳腺癌的不良預(yù)后存在密切相關(guān)性?；谠谀[瘤中高表達(dá)并促進(jìn)其發(fā)生發(fā)展的重要作用，以及作為乳腺癌的標(biāo)志物和潛在治療靶點的重要價值，因此未來開發(fā)靶向FSCN1的干預(yù)措施，能為腫瘤治療尤其是乳腺癌的治療提供可靠的策略。

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The role and regulatory mechanism of FSCN1 in breast tumorigenesis and progression

Dong Chang1, Xiangxiang Liu1, Rui Liu2, Jianwei Sun1

FSCN1, an actin-bundling protein,is highly expressed in almost all metastatic tumors and is associated with the poor prognosis. In breast cancer FSCN1 is highly expressed in basal-like and triple negative subgroups. There is significant progress in understanding the role of fascin in breast cancer. Studies on FSCN1 in recent years have revealed that FSCN1 not only promotes tumor migration, invasion, metastic colonization, cancer cell self-renewal and drug resistance, but also regulates glucose and lipid metabolism and mitochondrial remodeling in tumor cells. In this review, we focus on the structure and regulatory mechanism of FSCN1 in breast tumorigenesis and metastasis, and discuss the clinical value of FSCN1 with the aim to provide a direction for further research in this field.

FSCN1; actin bundle; breast cancer; tumorigenesis; tumor progression

2022-11-01;

2022-12-27;

2022-12-28

國家自然科學(xué)基金項目(編號：82273460, 32260167)，云南省應(yīng)用基礎(chǔ)研究基金(編號：202101AV070002, 2019FY003030)，云南省科技計劃重大專項(編號：202102AA310055)，云南大學(xué)研究生科研創(chuàng)新項目(編號：ZC-22223017, KC-22222424)和國家衛(wèi)生健康委毒品依賴和戒治重點實驗室開放課題(編號：2020DAMOP-005)項目資助[Supported by the National Natural Science Foundation of China (Nos. 82273460, 32260167), the Applied Basic Research Foundation of Yunnan Province (No. 202101AV070002, 2019FY003030), the Major Science and Technique Programs in Yunnan Province (No. 202102AA310055), the Graduate Scientific Research Innovation Project of Yunnan University (Nos. ZC-22223017, KC-22222424), and the NHC Key Laboratory of Drug Addiction Medicine (No. 2020DAMPO-005)]

常棟，碩士研究生，研究方向：生物與醫(yī)藥。E-mail: 13648831440@139.com

孫建偉，博士，教授，研究方向：腫瘤發(fā)生與轉(zhuǎn)移機(jī)制研究。E-mail: jwsun@ynu.edu.cn

10.16288/j.yczz.22-346

(責(zé)任編委: 宋質(zhì)銀)