FSCN1在乳腺癌發(fā)生發(fā)展中的作用及其調控機制

常棟，劉享享，劉睿，孫建偉

綜 述

FSCN1在乳腺癌發(fā)生發(fā)展中的作用及其調控機制

常棟1，劉享享1，劉睿2，孫建偉1

1. 云南大學生命科學學院，生命科學研究中心，昆明 650504 2. 昆明醫(yī)科大學第三附屬醫(yī)院乳腺外科，昆明 650118

FSCN1是一種肌動蛋白結合蛋白，能夠將肌動蛋白絲集成一束。FSCN1在幾乎所有的轉移性腫瘤中高表達，并與大部分腫瘤的不良預后密切相關。在基底樣和三陰性乳腺癌中高度表達。近年來關于FSCN1的報道愈發(fā)頻繁，隨著深入研究發(fā)現(xiàn)，F(xiàn)SCN1除了促進癌細胞的遷移、侵襲和轉移定植，維持癌細胞自我更新和增強耐藥性，還具有調控癌細胞的糖脂代謝及線粒體重塑等功能。本文從FSCN1的結構和調節(jié)形式，促進乳腺癌發(fā)生和轉移的分子機制，以及其在乳腺癌中的作用及功能展開介紹，最后對FSCN1在臨床上的價值進行了總結，為FSCN1在乳腺癌領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；腫瘤進展

據國際癌癥研究機構2021年發(fā)布的癌癥統(tǒng)計數據分析，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展，但仍有相當比例的乳腺癌患者復發(fā)[2]并且經歷轉移[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志物和有效的治療靶點，對改善患者的生存質量尤為關鍵。

腫瘤轉移是一個復雜、多步驟的過程。原發(fā)性腫瘤經過上皮–間質轉化(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的激活導致癌細胞間連接破壞、基質重組和基底膜的降解，并經歷細胞骨架的廣泛重塑等一系列的變化[4]。具有EMT特征的癌癥干細胞(cancer stem cells，CSCs)內滲到附近血管或淋巴，通過循環(huán)系統(tǒng)散播到遠處組織的微血管，少數“幸運”的癌細胞在適宜的條件下從微血管壁處逃逸并成功定植，形成轉移性腫瘤[5]。乳腺癌細胞更容易向骨、肝臟、肺、腦等部位轉移[6]，但不同乳腺癌亞型的轉移行為也各有特點[3]。

肌動蛋白作為細胞骨架蛋白，可以為細胞提供內部的機械支撐，驅動細胞運動并控制胞內物質運動的軌跡，對大多數細胞的生存至關重要[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)的細絲束成分中大小為55 kDa的蛋白同源[9]。作為一種關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，直接參與細胞運動和遷移、細胞–基質黏附、偽足形成等過程[10]。家族有三個亞型：表達于神經細胞、內皮細胞、間充質細胞和樹突狀細胞，而在正常的上皮細胞中不表達或低水平表達[11]，并在幾乎所有類型的轉移性癌癥中高表達[12]；在視網膜和耳中特異性表達，小鼠中的無義突變會導致進行性聽力損失和視網膜變性[13]；在睪丸及精子頭部特異性表達[14]。近年來，有關FSCN1在乳腺癌發(fā)生發(fā)展及轉移中的作用機制研究越來越多。本實驗室及其他實驗室的研究表明，高表達介導乳腺癌細胞的遷移、侵襲、轉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后密切相關，因此，F(xiàn)SCN1可作為某些類型乳腺癌的標志物和潛在的治療靶點[24～32]。本文將主要圍繞FSCN1的結構和調節(jié)形式，其促進乳腺癌發(fā)生和轉移的分子調控機制、在乳腺癌中行使的功能展開綜述，最后對FSCN1在臨床上的價值進行了探討和展望。

1 FSCN1的結構

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長的內含子1分隔；下游短外顯子2～4在0.8 kb范圍內間隔排列，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蛋白在進化上是高度保守的，表明FSCN1可能行使某些基本的生物學功能，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成四個串聯(lián)的β-三葉結構域(β-Trefoli)，N端和C端分別位于β-Trefoli1和β-Trefoli4上[34]。FSCN1具有三個不同的結合肌動蛋白的表面區(qū)域，其中兩個較大的肌動蛋白結合區(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合，ABS3結合第二個肌動蛋白絲[35,37]。

圖1 FSCN1的結構

A：FSCN1的基因結構，框內是參與轉錄后調控的microRNA(miRNA)。B：FSCN1蛋白的三維結構，ABS和β-Trefoli分別代表FSCN1的肌動蛋白結合區(qū)域和結構域，內側標注四個氨基酸殘基是FSCN1翻譯后修飾的主要位點。

2 FSCN1在乳腺癌中的調控

2.1 FSCN1的轉錄調控

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

2.1.1 JAK-STAT通路

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

在乳腺癌細胞(4T1、MDA-MB-231)中，STAT3作為轉錄因子通過響應白介素-6(interleukin6，IL-6)或抑瘤素M (oncostatin M，OSM)與的啟動子特異性結合來誘導的表達，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細胞中，經過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)在細胞核中形成蛋白復合物，并與啟動子的160bp保守區(qū)域上的STAT和NF-κB共同結合位點GGGGAA重疊序列結合以誘導其表達[41]，這說明STAT3/NF-κB復合物的形成有利于乳腺癌細胞中的表達。

最近的研究發(fā)現(xiàn)一些化合物可以特異性抑制JAK-STAT通路來下調的表達。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結構域(src homology 2 domain)相互作用抑制STAT3的二聚化，進而下調MDA- MB-231細胞中的水平。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誘導的JAK2或STAT3的磷酸化來降低STAT3的磷酸化水平，進而抑制的表達和TNBC細胞的遷移和侵襲。

2.1.2 NF-κB通路

NF-κB被認為是慢性炎癥引起某些腫瘤進展的關鍵因子，在腫瘤中NF-κB發(fā)揮調控癌細胞的增殖和存活、EMT以及血管生成等多種作用[44]。在乳腺癌中NF-κB也是調控表達的關鍵轉錄因子。除了與STAT3協(xié)同作用促進的上調外，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因子2 (TNF receptor associatedfactor2, TRAF2)特異性結合并激活其E3泛素連接酶活性從而啟動經典的NF-κB信號通路[45]，也上調了的表達。此外，亮氨酸氨肽酶3 (leucineaminope-ptidase3, LAP3)通過阻斷p38-Hsp27通路促進NF-κB的激活，進而促進的上調[46]，因此，來自天然海產品的LAP3抑制劑可高效地抑制該通路引起的效應[47]。

圖2 調控FSCN1表達的相關信號通路

2.1.3 TGFβ-SMAD通路

入組標準：1）留守學生組 留守年限＞1年的留守學生進入本組；2）非留守學生組 在進入留守學生組的學生同一班級按1：1配對，隨機抽取性別、年齡相同的非留守學生進入本組。

轉化生長因子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節(jié)細胞命運的作用，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，并促進腫瘤的進展。在乳腺癌中，TGFβ信號通路也調控的表達。

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

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、調節(jié)細胞內轉運等基本細胞功能中起著關鍵作用；在腫瘤發(fā)生中，EGFR與有絲分裂信號和轉運失調有密切關聯(lián)[50]，同時EGFR介導的通路或信號軸對乳腺癌中的表達調控起到重要的作用。

在表皮生長因子(epidermalgrowthfactor, EGF)刺激后的TNBC細胞中，的mRNA和蛋白質表達水平均顯著增加，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和蛋白表達水平，并且可阻斷EGF對表達的促進作用[51]，這說明部分TNBC細胞系通過EGFR-MAPK通路介導FSCN1的上調從而促進TNBC的侵襲能力。

EGFR還介導Rab25對的調控作用：轉運蛋白Rab25 (ras-related protein 25)將β1整合素(integrinsubunitbeta1, ITGB1)從內體運輸到質膜，二者協(xié)調激活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[52]。作為EMT過程的核心轉錄因子之一，Snail與啟動子上的特定位點結合，最終引起的上調，進而促進乳腺癌的侵襲和轉移。

作為EGF超家族中的一員，TGFα也可能通過EGFR介導的表達：有報道稱，TGFα消除了糖皮質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大鼠乳腺上皮腫瘤細胞中類固醇誘導的的下調[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)生的主要調節(jié)途徑，在調控腫瘤干細胞活性方面起重要作用[54]。由于癌細胞的干性特征，因此經常發(fā)現(xiàn)Wnt信號途徑的突變，乳腺癌中異?；钴S的Wnt信號下游轉錄因子也導致了的過表達。

佛波酯蛋白激酶C激活劑(tissue plasminogen activator, TPA)在乳腺癌細胞(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Wnt1表達從而誘導細胞遷移[55]，伴隨著Wnt信號通路的開啟表達也相應的上調，二十二碳六烯酸(docosahexaenoicacid, DHA)通過減弱PKC和Wnt1介導的的表達而有效地抑制TPA誘導的細胞遷移。此外，表皮生長因子受體2(erb-B2 receptor tyrosine kinase 2, ERBB2)過表達可能通過促進Wnt/β-catenin信號通路來增強的轉錄活性，在此過程中，NF-κB也有一定程度的上調[56]。還有報道稱沙棗提取物抑制ERBB2表達和β-catenin的磷酸化，這在一定程度上抑制了的過表達[57]。

2.1.6 RhoA-ROCK1軸

定位在細胞-細胞外基質粘附位點的Ras抑制蛋白1(ras suppressor protein 1，RSU-1)在乳腺癌細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)-軸促進表達[58]，并且RSU-1可能通過GDF-15將Ras信號通路與肌動蛋白細胞骨架調節(jié)聯(lián)系起來，但具體的機制仍需進一步探究。

2.2 FSCN1的轉錄后調控

在乳腺癌中，miRNA參與的轉錄后調控(圖1A)。譬如miR-133a、miR-145、miR488等miRNA與mRNA的3′UTR結合抑制其轉錄活性或使其mRNA降解[59-61]，miR-30a間接調控的轉錄活性[62]，X-連鎖凋亡蛋白抑制因子(X-linked inhibitor of apoptosis, XIAP)的3′UTR可以作為內源競爭RNA(competingendogenousRNA, ceRNA)競爭性結合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)，食管鱗癌細胞(KYSE-150)的增殖、遷移和絲狀偽足的形成能力均明顯增強，并且Ser38和Ser39殘基的雙重去磷酸化突變能最大限度地促進食管鱗狀細胞癌(esophagealsquamouscellcarcinoma, ESCC)細胞的增殖、遷移和絲足的形成；Villari等[67]證明Ser274是FSCN1介導微管結合的關鍵殘基，該殘基的去磷酸化突變導致FSCN1與微管的高度穩(wěn)定結合。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)合調控細胞的行為。關于FSCN1磷酸化的修飾機制仍有待進一步的探討。Cheng等[68]最近發(fā)現(xiàn)FSCN1在人胚胎腎細胞(HEK-293T)和食管鱗癌細胞(KYSE140)中與乙?；D移酶P300/CBP相關因子(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?；?。FSCN1的Lys471乙?；軌蝻@著抑制體外某些食管癌細胞遷移和小鼠體內的腫瘤轉移，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。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，進而抑制了結直腸癌上皮細胞(DLD-1)的體外遷移。

3 FSCN1在乳腺癌中的功能

3.1 調控遷移、侵襲和轉移

EMT是原發(fā)腫瘤細胞獲得轉移能力的核心步驟之一。細胞骨架的廣泛重塑、細胞間連接破壞、細胞外基質重組等一系列深刻的變化使癌細胞獲得更強的運動能力，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：促進乳腺癌細胞的遷移、侵襲和轉移。

通過對BALB/c鼠的尾靜脈注射4T1細胞，在一段時間后用克隆形成實驗檢測肺轉移4T1細胞的數量發(fā)現(xiàn)，相較于對照組而言，敲降組的細胞轉移數量更少[16,20]。將攜帶熒光素酶的MDA-MB-231細胞通過尾靜脈注射到一種免疫缺陷鼠(NOD-SCID鼠)中，在40天內通過活體成像觀察不同小鼠的肺轉移信號強度發(fā)現(xiàn)，與FSCN1敲降組小鼠相比，對照組的肺轉移信號明顯較強，尤其在40天時[16]。一些乳腺癌細胞系的遷移和侵襲試驗也是過表達促進乳腺癌細胞遷移和侵襲的佐證[23,45,47,70]。這些證據都表明了過表達增強了不同類型乳腺癌細胞的轉移能力，并且FSCN1能與其他肌動蛋白相關蛋白相互協(xié)助以進一步的促進乳腺癌細胞的運動[17]。但有報道稱高表達促進MDA-MB-231細胞的轉移與其肌動蛋白捆綁活性無關[71]，這與大多數證據相矛盾，并且只突變Ser39這一肌動蛋白結合位點不足夠有說服力。當然FSCN1也可能通過獨立于肌動蛋白集束功能的其他功能促進腫瘤細胞轉移，這需要更進一步的探索。

3.2 維持癌細胞干性和化療耐藥

大鼠白細胞分化抗原44(CD44)high、大鼠白細胞分化抗原24(CD24)low[72]及乙醛脫氫酶(aldehydedehydrogenase, ALDH)high[73]經常作為鑒定乳腺癌干細胞的標記物。在MDA-MB-231細胞中將敲降后，調節(jié)胚胎干細胞多能性的SRY-盒轉錄因子(SRY-box transcription factor 2, Sox2)等水平下調，乳腺癌中調節(jié)細胞自我更新的Notch通路及其下游靶標也有明顯的下調[19]，F(xiàn)SCN1陽性的乳腺癌細胞集落形成能力更強，在裸鼠中皮下成瘤的體積更大，并且FSCN1與CD44high/CD24low或ALDHhigh干細胞標志物的表達無關，這揭示了FSCN1通過激活Notch通路維持癌癥干細胞的自我更新能力。耐藥性是腫瘤干細胞的關鍵特征之一，將敲降和正常的MDA-MB-231細胞注射到裸鼠體內后化療三個周期后，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在部分乳腺癌細胞中通過介導粘著斑激酶(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]參與乳腺癌細胞的干性維持和化療耐藥。

3.3 癌細胞增殖和腫瘤生長

有報道稱FSCN1在乳腺癌細胞(MDA-MB-435和MDA-MB-231)中異位表達增強了細胞的增殖能力[22]，并且在膽管癌、黑色素瘤及某些肺癌細胞中[75-77]FSCN1也具有調控細胞增殖的作用。Chen等[16]將4T1細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，這說明在體外4T1的增殖似乎與FSCN1無關。Hayashi、Xu等[78,79]在肝細胞癌和胰腺癌中將敲除或異位表達后對細胞的增殖幾乎沒有影響。當然，鑒于不同腫瘤細胞系間的異質性，在不同的癌癥類型及同種類型的不同細胞系中FSCN1表達與細胞增殖的關系也不盡相同，F(xiàn)SCN1與癌細胞增殖的關系仍亟待未來進一步的探索。

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及生理學細節(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，尋找合適的生物標志物來改善乳腺癌診斷、預后和治療監(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測不良預后和腫瘤診斷標記物的價值(表1)，同時結合其在腫瘤細胞中高表達的特點[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志物，以用于乳腺癌的風險評估、診斷、預后，并用于預測治療效果和復發(fā)情況。已有證據表明，針對FSCN1的小分子抑制劑能夠有效的阻斷FSCN1引起的癌細胞遷移、侵襲和轉移(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胞的遷移能力，其通過占據FSCN1的肌動蛋白結合位點來抑制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細胞的肺定植減少了80%以上，同時也減少了4T1細胞的肺定植[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[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、侵襲和轉移的功能，這些小分子化合物為靶向FSCN1抗腫瘤轉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，直接參與細胞運動和遷移等過程[10]，并促進了大多數類型癌癥的發(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的表達，的過表達會促進乳腺癌細胞遷移和侵襲能力，有利于乳腺癌的遠端轉移和定植，并賦予乳腺癌細胞維持干性和化療耐藥的能力。最近有研究表明FSCN1增強了鐵死亡誘導劑愛拉斯汀(Erastin)誘導的MDA-MB-231細胞鐵死亡的易感性[90]，這可能會為TNBC患者提供一個有潛力的治療方向。FSCN1與腫瘤細胞的代謝也存在密切聯(lián)系，此前本實驗室證明了FSCN1介導線粒體重塑及維持線粒體DNA穩(wěn)定來促進線粒體氧化磷酸化[91]；在結直腸癌中，的敲除會導致編碼脂肪酸合成關鍵酶的脂肪酸合酶(fattyacidsynthase, FASN)和硬脂酰–輔酶A去飽和酶(stearoyl-CoAdesaturase，SCD)基因表達下調[92]；在非小細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)軸來促進糖酵解[93,94]。另外有研究表明FSCN1通過增強YAP1的機械轉導能力以促進膽管癌的發(fā)展[95]，綜合基因組學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通路促進腫瘤發(fā)生發(fā)展。另外，F(xiàn)SCN1還具有介導機械轉導、調節(jié)核仁形態(tài)和染色質修飾的功能[81]，最新的研究表明，F(xiàn)SCN1能夠動態(tài)的進出細胞核，其進入核內會與組蛋白H3直接結合，并促進核F-actin的集束，以及促進癌細胞DNA損傷后的DNA損傷應答[97]。這些研究結果說明FSCN1在腫瘤發(fā)生及惡化中具有復雜而重要的作用，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，仍需要進一步的深入研究。

目前大量的研究表明的高表達水平與乳腺癌的不良預后存在密切相關性?；谠谀[瘤中高表達并促進其發(fā)生發(fā)展的重要作用，以及作為乳腺癌的標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

國家自然科學基金項目(編號：82273460, 32260167)，云南省應用基礎研究基金(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)生與轉移機制研究。E-mail: jwsun@ynu.edu.cn

10.16288/j.yczz.22-346

(責任編委: 宋質銀)