STIM1在腫瘤發(fā)生及轉(zhuǎn)移中的研究進(jìn)展

嚴(yán)程浩，白韋鈺，張智猛，沈俊嶺，王友軍，孫建偉

綜 述

STIM1在腫瘤發(fā)生及轉(zhuǎn)移中的研究進(jìn)展

嚴(yán)程浩1，白韋鈺1，張智猛1，沈俊嶺1，王友軍2，孫建偉1

1. 云南大學(xué)生命科學(xué)中心，生命科學(xué)學(xué)院，省部共建云南生物資源保護(hù)與利用國(guó)家重點(diǎn)實(shí)驗(yàn)室，昆明 650500 2. 北京師范大學(xué)生命科學(xué)學(xué)院，基因資源與分子發(fā)展北京重點(diǎn)實(shí)驗(yàn)室，北京 100875

基質(zhì)互作分子1 (stromal interaction molecule 1，STIM1)是細(xì)胞鈣庫(kù)操縱性鈣內(nèi)流(store-operated calcium entry，SOCE)通路的關(guān)鍵成員，它定位在內(nèi)質(zhì)網(wǎng)膜上，并在多種腫瘤細(xì)胞中高表達(dá)。異常表達(dá)的STIM1能夠通過影響侵襲偽足(invadopodia)形成、干擾血管生成、介導(dǎo)炎癥反應(yīng)、改變細(xì)胞骨架和細(xì)胞動(dòng)力等方式促進(jìn)腫瘤發(fā)生及轉(zhuǎn)移，然而其具體的調(diào)控作用機(jī)制仍未完全闡明。本文綜述了目前STIM1在不同腫瘤發(fā)生及轉(zhuǎn)移中的最新研究進(jìn)展，總結(jié)并探討了其在腫瘤發(fā)生及轉(zhuǎn)移中的調(diào)控機(jī)制，為將來在腫瘤領(lǐng)域?qū)TIM1的深入研究提供借鑒和參考。

STIM1；鈣庫(kù)操縱性鈣內(nèi)流；腫瘤發(fā)生；腫瘤轉(zhuǎn)移

基質(zhì)互作分子1(stromal interaction molecule 1，STIM1)是一種位于內(nèi)質(zhì)網(wǎng)膜上的單次跨膜鈣離子結(jié)合蛋白。其保守程度很高，最初被定義為一種與血細(xì)胞前體相互作用的基質(zhì)細(xì)胞表面分子[1]，隨后被鑒定為參與激活鈣離子流入所必要的一員[2]。STIM1被發(fā)現(xiàn)在膠質(zhì)母細(xì)胞瘤[3]、胰腺癌[4]、前列腺癌[5,6]、肝細(xì)胞癌[7]、腎透明細(xì)胞癌[8]中高表達(dá)，并促進(jìn)癌細(xì)胞增殖、遷移、侵襲和凋亡抵抗。同時(shí)，功能喪失性突變會(huì)導(dǎo)致患者T細(xì)胞激活的嚴(yán)重缺陷，伴隨著感染易感性增加。因此，STIM1對(duì)維持正常免疫系統(tǒng)穩(wěn)定具有一定的作用。另外，STIM1還能幫助內(nèi)皮細(xì)胞增殖[9]。研究發(fā)現(xiàn)，高表達(dá)的STIM1能夠促進(jìn)血管生成、腫瘤發(fā)生、腫瘤轉(zhuǎn)移[10]以及癌細(xì)胞耐藥。近年來，關(guān)于STIM1在腫瘤發(fā)生及轉(zhuǎn)移中的作用機(jī)制研究越來越多，本文總結(jié)了STIM1在腫瘤發(fā)生及轉(zhuǎn)移中的功能，并對(duì)其調(diào)控機(jī)制的研究進(jìn)展進(jìn)行了綜述。

1 STIM1的生物學(xué)功能

1.1 STIM1介導(dǎo)Ca2+內(nèi)流

細(xì)胞內(nèi)Ca2+水平的變化能夠提供普遍和動(dòng)態(tài)的信號(hào)，從而調(diào)節(jié)大多數(shù)細(xì)胞中的各種生物過程[11,12]。Ca2+參與了細(xì)胞的眾多生理反應(yīng)，包括細(xì)胞活化、分化和胞吐作用[13,14]。STIM1主要定位于內(nèi)質(zhì)網(wǎng)，且在質(zhì)膜中也有分布[15～18]。靜息狀態(tài)下的內(nèi)質(zhì)網(wǎng)如果處于鈣儲(chǔ)備充足狀態(tài)，位于其上的Ca2+會(huì)與STIM1-EF手形結(jié)構(gòu)域結(jié)合。EF手形結(jié)構(gòu)域與SAM結(jié)構(gòu)域具有穩(wěn)定的相互作用，能夠維持STIM1分子內(nèi)質(zhì)網(wǎng)腔部分的單體分布[19]。STIM1在內(nèi)質(zhì)網(wǎng)中擔(dān)任Ca2+的傳感器，是SOCE的開關(guān)。內(nèi)質(zhì)網(wǎng)鈣庫(kù)的消耗導(dǎo)致STIM1的構(gòu)象變化和寡聚，并使其在內(nèi)質(zhì)網(wǎng)膜上的分布發(fā)生顯著變化，從普遍的擴(kuò)散分布改變?yōu)榻咏|(zhì)膜(plasma membrane，PM)的離散簇(puncta)[20～22]。激活的STIM1結(jié)合并偶聯(lián)質(zhì)膜上SOCE通道蛋白Orai1形成內(nèi)質(zhì)網(wǎng)鈣釋放激活鈣(calcium release activated calcium channel，CRAC)通道[23,24]。由STIM1和Orai1組成的CRAC通道在內(nèi)質(zhì)網(wǎng)與質(zhì)膜連接區(qū)域介導(dǎo)鈣離子的內(nèi)流，并能在Orai1通道口處產(chǎn)生Ca2+微域[23]。內(nèi)質(zhì)網(wǎng)鈣庫(kù)Ca2+水平降低后STIM1被激活，并與Orai1以協(xié)同的方式在內(nèi)質(zhì)網(wǎng)和質(zhì)膜中形成緊密相對(duì)的簇狀復(fù)合物，從而為SOCE的局部激活提供物理基礎(chǔ)。這是理解高度局部化的SOCE信號(hào)的下游分子和生理功能的關(guān)鍵。

1.2 STIM1維持內(nèi)皮細(xì)胞增殖

內(nèi)皮細(xì)胞的遷移、增殖、極性、分化和細(xì)胞間通信水平上的協(xié)調(diào)控制對(duì)功能性血管形態(tài)發(fā)生至關(guān)重要[25]。Abdullaev等[9]發(fā)現(xiàn)，與基因沉默均可抑制內(nèi)皮細(xì)胞的增殖，并導(dǎo)致細(xì)胞周期停滯在S期或G2期，表明STIM1參與的SOCE在維持內(nèi)皮細(xì)胞增殖方面具有重要作用。

1.3 STIM1維持免疫系統(tǒng)穩(wěn)定

Ca2+通過CRAC通道流入細(xì)胞內(nèi)部激活淋巴細(xì)胞和免疫反應(yīng)[26～28]。Picard等[29]發(fā)現(xiàn)，缺陷的患者會(huì)伴隨原發(fā)性免疫缺陷，更容易受到病毒和細(xì)菌感染，而缺陷的小鼠則更容易患有包括脾腫大、淋巴結(jié)病、白細(xì)胞器官浸潤(rùn)、皮炎和瞼緣炎在內(nèi)的病癥[30]。這些表型歸因于活化T細(xì)胞蛋白的Ca2+流入異常導(dǎo)致的功能抑制和調(diào)節(jié)性T細(xì)胞發(fā)育和功能缺陷。

此外，STIM1介導(dǎo)的SOCE在調(diào)節(jié)中性粒細(xì)胞煙酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶的激活和隨后的活性氧(ROS)的產(chǎn)生以及肥大細(xì)胞的激活、脫顆粒和細(xì)胞因子的分泌中發(fā)揮了關(guān)鍵作用[31,32]。

Berry等[33]的研究表明，在B細(xì)胞中SOCE對(duì)于抗凋亡蛋白的轉(zhuǎn)錄和上調(diào)至關(guān)重要。B細(xì)胞受體(B cell receptor，BCR)刺激STIM1，STIM2均缺失的B細(xì)胞會(huì)導(dǎo)致大量細(xì)胞死亡。其具體作用機(jī)制是，BCR介導(dǎo)的SOCE激活了NFAT和核因子-kappaB (NF-κB)通路，最終聚集在哺乳動(dòng)物雷帕霉素復(fù)合物1(mTORC1)靶點(diǎn)上，激活并誘導(dǎo)c-Myc從而驅(qū)動(dòng)B細(xì)胞增殖。

STIM1和Orai1介導(dǎo)的Ca2+內(nèi)流對(duì)T細(xì)胞的激活、增殖和代謝至關(guān)重要，過度或延長(zhǎng)的Ca2+信號(hào)可導(dǎo)致細(xì)胞死亡[34]。Desvignes等[35]發(fā)現(xiàn)，在受到慢性結(jié)核分枝桿菌感染的小鼠中，STIM1缺乏的T細(xì)胞對(duì)T細(xì)胞受體(T cell receptor，TCR)刺激下的死亡產(chǎn)生抗性，肺部促凋亡因子FAS (fas cell surfacedeath receptor)、FASL (fas ligand)和NOXA (phorbol-12- myristate-13-acetate-induced protein 1)的表達(dá)顯著。SOCE是T細(xì)胞免疫所需的鈣離子進(jìn)入的主要途徑。STIM1、STIM2和Oria1介導(dǎo)的SOCE是中心激活因子，它產(chǎn)生關(guān)鍵的Ca2+微域，這是活化T細(xì)胞核因子(nuclear factor of activated T cells，NFAT)核易位和最佳細(xì)胞因子基因表達(dá)、代謝和增殖所必需的。

1.4 STIM1與脂質(zhì)信號(hào)傳遞

眾所周知，內(nèi)質(zhì)網(wǎng)(endoplasmic reticulum，ER)與質(zhì)膜界面的連接是通過脂質(zhì)轉(zhuǎn)運(yùn)實(shí)現(xiàn)的，脂質(zhì)轉(zhuǎn)運(yùn)的位點(diǎn)則由PI、PI4P、PA、PS、PC和甾醇等各種脂質(zhì)轉(zhuǎn)運(yùn)蛋白介導(dǎo)[36]。

內(nèi)質(zhì)網(wǎng)與質(zhì)膜接觸位點(diǎn)中的Ca2+與脂質(zhì)信號(hào)之間存在密切的相互作用和反饋回路。Weber-Boyvat等[37]發(fā)現(xiàn)，生理?xiàng)l件下，氧甾醇結(jié)合蛋白相關(guān)蛋白3 (oxysterol-binding protein related proteins 3，ORP3)參與脂質(zhì)運(yùn)輸和細(xì)胞信號(hào)傳導(dǎo)。ORP3定位于ER-PM界面，與脂質(zhì)轉(zhuǎn)運(yùn)和局部粘附動(dòng)力學(xué)有關(guān)。它在蛋白激酶C激活時(shí)易位到連接點(diǎn)進(jìn)行連接，并與Ca2+一起產(chǎn)生協(xié)同效應(yīng)。沉默后顯著影響ORP3移位到ER-PM多克隆位點(diǎn)(multiple cloning site，MCS)的水平。STIM1在ORP3招募中發(fā)揮作用[38]，過度表達(dá)的STIM1會(huì)促進(jìn)和擴(kuò)大ER-PM接觸區(qū)域以增加ORP3與PM的關(guān)聯(lián)，從而影響ORP3發(fā)揮作用[39]。

2 STIM1在不同腫瘤中的作用

STIM1廣泛表達(dá)于人類各種組織，并參與到各種生理和病理過程。TCGA數(shù)據(jù)分析顯示，STIM1在人不同腫瘤如消化系統(tǒng)腫瘤中的膽管癌、胰腺癌，泌尿系統(tǒng)腫瘤中的腎嫌色細(xì)胞瘤、腎透明細(xì)胞癌、腎乳頭狀細(xì)胞癌，神經(jīng)系統(tǒng)腫瘤中的嗜鉻細(xì)胞瘤和副神經(jīng)瘤等中均高表達(dá)(圖1)，并與腫瘤的病理分型、惡性程度、侵襲性和轉(zhuǎn)移等都有相關(guān)性。

圖1 STIM1在不同腫瘤組織與配對(duì)正常組織中的表達(dá)水平

數(shù)據(jù)來自于http://gepia2.cancer-pku.cn。*表示<0.05。

2.1 STIM1與腫瘤發(fā)生

腫瘤發(fā)生是一個(gè)復(fù)雜的生物學(xué)過程，涉及到的影響因素眾多，STIM1可從以下幾個(gè)方面影響腫瘤的發(fā)生。

STIM1影響血管生成，從而促進(jìn)腫瘤發(fā)生。STIM1間接參與內(nèi)皮祖細(xì)胞(endothelial progenitor cells，EPCs)從骨髓中的招募，以維持腫瘤血管生成并促進(jìn)腫瘤發(fā)生。Lodola等[40]在腎細(xì)胞癌中發(fā)現(xiàn)，由STIM1和Orai1介導(dǎo)的SOCE能夠通過控制祖細(xì)胞增殖和血小管的形成來調(diào)節(jié)人類EPCs的生長(zhǎng)(圖2A，①和②)。Ye等[41]發(fā)現(xiàn)，EB病毒(epstein-barr virus，EBV)通過激活SOCE促進(jìn)鼻咽癌(nasophar-yngeal carcinoma，NPC)的腫瘤血管生成(圖2A，③)，并且STIM1在EBV陽(yáng)性鼻咽癌細(xì)胞系中高表達(dá)。利用表皮生長(zhǎng)因子(epidermal growth factor，EGF)治療后，在EBV陽(yáng)性NPC細(xì)胞中敲除STIM1可以顯著降低Ca2+內(nèi)流和血管內(nèi)皮生長(zhǎng)因子的產(chǎn)生，同時(shí)抑制異種移植物生長(zhǎng)和血管生成，表明EBV通過激活STIM1依賴性Ca2+信號(hào)來促進(jìn)EGF誘導(dǎo)的絲裂原活化蛋白激酶(mitogen-activated protein kinase 1，ERK)1/2信號(hào)傳導(dǎo)(圖2A，④)，而阻斷這種信號(hào)傳導(dǎo)可能會(huì)抑制EBV促進(jìn)的鼻咽癌血管生成。另有研究表明，STIM1可以與致瘤性和血管生成生長(zhǎng)因子啟動(dòng)的信號(hào)級(jí)聯(lián)作用，從而啟動(dòng)腫瘤的發(fā)生過程[42]。已知表皮生長(zhǎng)因子通過磷酸酯酶C (phospholipase C，PLC)/三磷酸肌醇(inositol 1,4,5-trisphosphate，IP3)通路刺激細(xì)胞內(nèi)Ca2+的釋放，導(dǎo)致SOCE的激活(圖2A，④)。Kokoska等[43]發(fā)現(xiàn)，非甾體抗炎藥物阻斷由EGF誘導(dǎo)的SOCE激活過程，從而干擾細(xì)胞增殖，抑制結(jié)直腸癌的發(fā)生，這獨(dú)立于其對(duì)前列腺素合成的抑制途徑。

STIM1參與的細(xì)胞內(nèi)一系列信號(hào)串?dāng)_(signal crosstalk)能夠影響腫瘤發(fā)生。Feng等[44]報(bào)道了Orai1與分泌途徑Ca2+-ATP酶2(secretory pathway Ca2+-ATPases2，SPCA2)相關(guān)信號(hào)通路，在該信號(hào)通路中，Orai1-SPCA2復(fù)合物的形成引發(fā)了一個(gè)能不依賴于鈣庫(kù)并自發(fā)激活獨(dú)立的Ca2+進(jìn)入通路，該通路調(diào)節(jié)乳腺癌腫瘤的發(fā)生(圖2A，⑤)。實(shí)際上，STIM1-Orai1作為一種“經(jīng)典”的信號(hào)通路，在雌激素受體陰性乳腺癌細(xì)胞生成中占主導(dǎo)地位[45]。SOCE是一個(gè)信號(hào)復(fù)合體，其功能改變是由STIM1在內(nèi)的數(shù)個(gè)信號(hào)組成單位決定的。異常的SOCE激活會(huì)促進(jìn)腫瘤發(fā)生與進(jìn)展。

STIM1與細(xì)胞骨架相關(guān)蛋白協(xié)同作用，影響腫瘤發(fā)生。微管完整性對(duì)于STIM1運(yùn)輸?shù)劫|(zhì)膜以及與組成SOCE必需的亞單位Orai1的相互作用是必要的。Chen等[46]發(fā)現(xiàn)，微管相關(guān)組蛋白去乙?；? (histone deacetylase 6，HDAC6)在宮頸癌細(xì)胞和正常宮頸上皮細(xì)胞之間對(duì)STIM1介導(dǎo)的SOCE的激活進(jìn)行差異調(diào)節(jié)(圖2A，⑦)，而大多數(shù)宮頸癌組織過度表達(dá)STIM1和Orai1，并伴有低乙酰化的α-微管蛋白，同時(shí)，HDAC6-STIM1相關(guān)通路能夠影響惡性細(xì)胞血管的生成。

2.2 STIM1與腫瘤轉(zhuǎn)移

細(xì)胞遷移是細(xì)胞和組織內(nèi)穩(wěn)態(tài)的基礎(chǔ)，并在許多生理和病理過程中起著關(guān)鍵作用。傷口愈合、免疫監(jiān)視和血管生成分別需要成纖維細(xì)胞、免疫細(xì)胞和內(nèi)皮細(xì)胞的遷移[47～50]，也有一些病理表型涉及“錯(cuò)誤”細(xì)胞類型的遷移，這與癌癥的進(jìn)展尤為相關(guān)。腫瘤細(xì)胞的遷移活動(dòng)是轉(zhuǎn)移級(jí)聯(lián)反應(yīng)中的一個(gè)關(guān)鍵步驟，它會(huì)導(dǎo)致腫瘤細(xì)胞在遠(yuǎn)處器官中的定植[51～53]。細(xì)胞運(yùn)動(dòng)遵循運(yùn)動(dòng)軸以及細(xì)胞骨架的極化方向，并受到膜動(dòng)力學(xué)的調(diào)節(jié)[54～58]，這在一定程度上是由遷移細(xì)胞的細(xì)胞內(nèi)鈣濃度([Ca2+]i)的梯度介導(dǎo)的。STIM/Orai蛋白作為膜蛋白，具有感知和反應(yīng)腫瘤微環(huán)境中已知發(fā)生的各種細(xì)胞內(nèi)和細(xì)胞外刺激的能力[59]。這些刺激因素包括：(1)缺氧，以及由此產(chǎn)生的氧化應(yīng)激(圖2B，①)；(2)ROS(圖2B，②)；(3)ADP核糖(adenosine diphosphate，ADPr)(圖2B，③)。研究發(fā)現(xiàn)，STIM1可以介導(dǎo)ROS和Ca2+(作為應(yīng)力反應(yīng)信使)之間的耦合(圖2B，④)[60]。

轉(zhuǎn)移與侵襲常被視為腫瘤進(jìn)展的兩個(gè)標(biāo)志，STIM1在促腫瘤侵襲方面也有重要作用。近年來，大量研究表明，基因突變有可能是黑色素瘤發(fā)生的一大誘因。全基因組分析顯示，在黑色素瘤患者的眾多突變基因的樣本中，B-Raf原癌基因(B-Raf proto-oncogene，BRAF)突變頻率最高，占比約為52%[61]。BRAF最常見突變類型為BRAF- V600E[62]，小分子抑制劑威羅菲尼(vemurafenib)靶向BRAF-V600E以抑制含有此突變類型的黑色素瘤[63]，但長(zhǎng)期使用會(huì)產(chǎn)生耐藥性[64]，Shen等[10]發(fā)現(xiàn)STIM1在威羅菲尼耐藥細(xì)胞當(dāng)中高表達(dá)，隨后激活下游丙酮酸激酶2 (pyruvate kinase2，PK2)-原癌基因SRC(SRC proto-oncogene)信號(hào)軸，從而啟動(dòng)侵襲偽足的形成，導(dǎo)致抗藥性產(chǎn)生引起的腫瘤轉(zhuǎn)移(圖2B)，將STIM1敲除后，侵襲偽足形成顯著下降，表明STIM1/Ca2+信號(hào)通過影響侵襲偽足的形成調(diào)控腫瘤轉(zhuǎn)移。

圖2 STIM1在腫瘤發(fā)生與轉(zhuǎn)移中的作用

A：STIM1與腫瘤發(fā)生。①STIM1和Orai1介導(dǎo)的SOCE控制祖細(xì)胞增殖；②STIM1和Orai1介導(dǎo)的SOCE影響血小管的形成；③EB病毒通過激活STIM1依賴性Ca2+信號(hào)促進(jìn)EGF誘導(dǎo)的ERK1/2信號(hào)傳導(dǎo)，促進(jìn)鼻咽癌中的腫瘤血管生成；④表皮生長(zhǎng)因子通過PLC/IP3通路刺激細(xì)胞內(nèi)Ca2+的釋放，導(dǎo)致SOCE的激活；⑤Orai1-SPCA2復(fù)合物的形成引發(fā)了一個(gè)不依賴于鈣庫(kù)并自發(fā)獨(dú)立激活的Ca2+進(jìn)入通路，調(diào)節(jié)乳腺癌腫瘤的發(fā)生；⑥HIF-1α與STIM1啟動(dòng)子結(jié)合，并調(diào)控其在PANC-1癌細(xì)胞中的表達(dá)；⑦HDAC6在宮頸癌細(xì)胞和正常宮頸上皮細(xì)胞之間對(duì)STIM1介導(dǎo)的SOCE的激活進(jìn)行差異調(diào)節(jié)。B：STIM1與腫瘤轉(zhuǎn)移。①STIM1作為內(nèi)質(zhì)網(wǎng)膜蛋白，能夠感知和反應(yīng)腫瘤微環(huán)境中的缺氧刺激；②STIM1作為膜蛋白，能夠感知和反應(yīng)腫瘤微環(huán)境中的ROS刺激；③STIM1介導(dǎo)ROS和Ca2+(作為應(yīng)力反應(yīng)信使)之間的耦合；④STIM1作為膜蛋白，能夠感知和反應(yīng)腫瘤微環(huán)境中的ADPr刺激；⑤威羅菲尼耐藥細(xì)胞當(dāng)中STIM1高表達(dá)，隨后激活下游Pyk2-Src信號(hào)軸，從而啟動(dòng)侵襲偽足的形成，導(dǎo)致抗藥性產(chǎn)生引起的腫瘤轉(zhuǎn)移。

STIM1在腫瘤發(fā)生和腫瘤進(jìn)展中發(fā)揮重要的作用(圖2)，是將來腫瘤研究中的重點(diǎn)和難點(diǎn)。

2.3 消化系統(tǒng)腫瘤

STIM1在多種消化系統(tǒng)腫瘤的患者組織中高表達(dá)，并促進(jìn)腫瘤細(xì)胞的侵襲及轉(zhuǎn)移。

胰腺導(dǎo)管腺癌(pancreatic ductal adenocarcinoma，PDAC)患者由于診斷較晚和治療耐藥性，5年生存率僅為7%～9%[65]，其一線治療劑為吉西他濱(gemcitabine)，但長(zhǎng)期治療會(huì)導(dǎo)致耐藥性。Kutschat等[66]發(fā)現(xiàn)，吉西他濱耐藥細(xì)胞顯示出相鄰的核糖核苷酸還原酶催化亞單位M1(ribonucleotide reductase catal-y-tic subunit M1，RRM1)和基因的共擴(kuò)增，較高的STIM1依賴性鈣內(nèi)流導(dǎo)致內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)受損，隨后激活NFAT。該工作揭示了STIM1作為變阻器的功能，能介導(dǎo)鈣信號(hào)參與調(diào)節(jié)生物過程，控制表觀遺傳細(xì)胞命運(yùn)的決定。Wang等[67]發(fā)現(xiàn)，與正常組織相比，STIM1和缺氧誘導(dǎo)因子-1alpha (hypoxia-inducible factor-1α，HIF-1α)在胰腺癌組織中表達(dá)上調(diào)。Kaplan-Meier實(shí)驗(yàn)顯示，HIF-1α和STIM1表達(dá)水平升高與無病生存期降低顯著相關(guān)，HIF-1α在癌組織的表達(dá)與STIM1的表達(dá)顯著正相關(guān)。此外，CHIP和熒光素酶檢測(cè)證實(shí)，HIF-1α與STIM1啟動(dòng)子結(jié)合，并調(diào)控其在PANC-1細(xì)胞中的表達(dá)(圖2A，⑥)。在結(jié)腸癌中，STIM1被Liang等[68]發(fā)現(xiàn)能夠促進(jìn)腸上皮增加杯狀細(xì)胞內(nèi)質(zhì)網(wǎng)壓力和因細(xì)胞損失引起的壓力，從而減弱細(xì)胞維持粘液層的能力，增加微生物暴露風(fēng)險(xiǎn)，導(dǎo)致結(jié)腸炎和結(jié)直腸癌的發(fā)生。Tang等[69]發(fā)現(xiàn)，在鱗狀食管癌(esophageal squamous cell carcinoma，ESCC)當(dāng)中，STIM1的高表達(dá)與ESCC的晚期腫瘤分級(jí)和不良預(yù)后相關(guān)。siRNA或化學(xué)抑制劑對(duì)STIM1表達(dá)的抑制顯著降低了ESCC細(xì)胞的活力和遷移能力。來自高通量單克隆抗體芯片、IHC芯片以及相關(guān)生存數(shù)據(jù)和功能分析的證據(jù)表明，STIM1在ESCC中是一個(gè)不良的預(yù)后生物標(biāo)志物。Xia等[70]關(guān)于胃癌的研究指出，較高的STIM1表達(dá)與晚期腫瘤的復(fù)發(fā)和死亡率密切相關(guān)，通過降低STIM1的表達(dá)水平，能夠降低兩種胃癌細(xì)胞系的增殖、代謝、遷移和侵襲。此外，基因的沉默也能改變異常的細(xì)胞周期和上皮-間充質(zhì)轉(zhuǎn)化(epithelial mesenchymal transition，EMT)的相關(guān)標(biāo)記物水平，提示STIM1促進(jìn)腫瘤細(xì)胞的增殖、代謝、遷移和侵襲，并可作為胃癌的不良預(yù)后標(biāo)志物。

2.4 泌尿系統(tǒng)腫瘤

腎細(xì)胞癌(renal cell carcinoma，RCC)是最常見的腎癌類型，占成人所患腫瘤[71,72]的2%～3%，腎細(xì)胞癌最常見的亞型是透明細(xì)胞腎細(xì)胞癌(clear cell renal cell carcinoma，ccRCC)[73]。Monteith等[74]發(fā)現(xiàn)，STIM1在ccRCC組織中高表達(dá)，STIM1通過常規(guī)的SOCE通路以增強(qiáng)ccRCC細(xì)胞的運(yùn)動(dòng)能力，加快細(xì)胞增殖和遷移速度，表明STIM1依賴的信號(hào)通路可能成為ccRCC治療干預(yù)的潛在預(yù)后標(biāo)志物和有吸引力的靶點(diǎn)。

2.5 神經(jīng)系統(tǒng)腫瘤

結(jié)節(jié)性硬化癥(tuberous sclerosis complex，TSC)是一種常染色體顯性綜合征，其特征是在包括大腦、腎臟、心臟和肺等廣泛的器官中伴隨著良性腫瘤的生長(zhǎng)[75]。Peng等[76]發(fā)現(xiàn)，通過過度活躍的mTORC1-STIM1級(jí)聯(lián)反應(yīng)而增強(qiáng)的SOCE可能有助于TSC相關(guān)腫瘤性質(zhì)向良性傾斜。因此，STIM1激動(dòng)劑能減弱mTOR抑制劑介導(dǎo)的AKT再活化，從而增強(qiáng)其治療TSC患者的療效。Pascual-Caro等[77]利用神經(jīng)母細(xì)胞瘤細(xì)胞SH-SY5Y進(jìn)行研究，發(fā)現(xiàn)STIM1是肌醇1,4,5-三磷酸受體3(inositol 1,4,5- trisphosphate receptor 3，ITPR3)基因表達(dá)的正調(diào)控因子。缺失導(dǎo)致ITPR3轉(zhuǎn)錄本和ITPR3蛋白水平顯著降低，從而導(dǎo)致線粒體游離Ca2+濃度降低，線粒體耗氧率降低，三磷酸腺苷(adenosine- triphosphate，ATP)合成率降低，加快腫瘤進(jìn)展。Pascual-Caro等[78]表明，STIM1在SH-SY5Y分化細(xì)胞中對(duì)細(xì)胞存活是絕對(duì)必要的，與野生型細(xì)胞相比，分化后的-KO細(xì)胞線粒體呼吸鏈復(fù)合物I活性顯著降低，線粒體內(nèi)膜去極化，線粒體游離Ca2+濃度降低，衰老水平升高。同時(shí)，-KO細(xì)胞在去極化時(shí)其Ca2+進(jìn)入增強(qiáng)，說明STIM1在保護(hù)SH-SY5Y細(xì)胞存活方面具有重要作用。Xie等[79]發(fā)現(xiàn)了STIM1的一個(gè)選擇性剪接變體STIM1β，它在神經(jīng)膠質(zhì)瘤組織中異常上調(diào)，以擾亂Ca2+信號(hào)通路，在功能上，STIM1β促進(jìn)膠質(zhì)母細(xì)胞瘤細(xì)胞的Ca2+流入，從而加快腫瘤細(xì)胞的增殖和生長(zhǎng)。

2.6 乳腺系統(tǒng)腫瘤

乳腺癌是全球最常見的診斷型癌癥，其發(fā)病率位居女性惡性腫瘤的首位[80]。Yang等[81]發(fā)現(xiàn)，Orai1和STIM1參與介導(dǎo)MDA-MB-231乳腺癌細(xì)胞中的庫(kù)容性鈣內(nèi)流，這對(duì)于體外乳腺腫瘤細(xì)胞遷移和小鼠腫瘤轉(zhuǎn)移至關(guān)重要。在動(dòng)物模型中，通過RNA干擾或抑制劑減弱SOCE，在轉(zhuǎn)移性強(qiáng)的人乳腺癌細(xì)胞內(nèi)減少Orai1或STIM1的表達(dá)均能夠減少腫瘤轉(zhuǎn)移，證明了Orai1和STIM1在腫瘤轉(zhuǎn)移中發(fā)揮作用。Pan等[82]發(fā)現(xiàn)，-KO可以通過直接抑制miR-145的表達(dá)，減少外泌體的產(chǎn)生，從而抑制胰島素受體底物1(insulin receptor substrate 1，IRS1)表達(dá)，以阻止異常的血管生成。Yang等[83]研究表明，乳腺癌患者中STIM1表達(dá)明顯高于鄰近非腫瘤組織。腫瘤大小、淋巴結(jié)轉(zhuǎn)移和雌激素受體陰性水平與STIM1過表達(dá)呈正相關(guān)。Cheng等[84]指出，在MDA-MB-231細(xì)胞中過表達(dá)STIM1能夠?qū)GF-β誘導(dǎo)的細(xì)胞周期阻滯和細(xì)胞增殖抑制恢復(fù)到與對(duì)照幾乎一致的水平，表明STIM1在TGF-β誘導(dǎo)的細(xì)胞增殖中發(fā)揮了關(guān)鍵作用。Chen等[85]研究發(fā)現(xiàn)，沉默抑制了活性局灶粘連激酶(focal adhesion kinase，F(xiàn)AK)和TLN1(talin1)在局灶粘連處的募集和關(guān)聯(lián)，表明整合素信號(hào)通路的力轉(zhuǎn)導(dǎo)被阻斷。表皮生長(zhǎng)因子誘導(dǎo)的肌球蛋白II調(diào)節(jié)輕鏈的磷酸化被STIM1的下調(diào)所消除，這說明肌動(dòng)球蛋白的形成依賴于STIM1介導(dǎo)的Ca2+進(jìn)入。更重要的是，STIM1能夠調(diào)控細(xì)胞收縮力的產(chǎn)生，這些結(jié)果突出了STIM1依賴的Ca2+信號(hào)通路通過調(diào)節(jié)肌動(dòng)球蛋白重組和增強(qiáng)的收縮力來控制細(xì)胞遷移的獨(dú)特作用。Huang等[86]發(fā)現(xiàn)的基因多態(tài)性與乳腺癌存在相關(guān)性。的風(fēng)險(xiǎn)G等位基因促進(jìn)了STIM1的高表達(dá)，的兩個(gè)無義替代突變r(jià)s3750996 G和rs2304891 A與乳腺癌的進(jìn)展相關(guān)。此外，Grady等[87]研究發(fā)現(xiàn)，Ca2+信號(hào)通路的正常生理活動(dòng)在癌癥中經(jīng)常被吸收和重塑，在受影響的細(xì)胞群中產(chǎn)生一個(gè)強(qiáng)大的致癌驅(qū)動(dòng)。細(xì)胞內(nèi)Ca2+水平的增加和降低都有可能增加細(xì)胞的惡性潛能，一些Ca2+信號(hào)通路的活性已被證明會(huì)影響化療反應(yīng)，這表明結(jié)合傳統(tǒng)化療與Ca2+靶向藥物的協(xié)同方法也能改善患者的預(yù)后水平，因此靶向調(diào)控相關(guān)Ca2+通路代表了精確醫(yī)學(xué)和乳腺癌癥治療的一種新方法。

2.7 其他系統(tǒng)腫瘤

STIM1在皮膚癌當(dāng)中也有重要的促瘤作用。紫外線照射的最直接后果是誘導(dǎo)嘧啶二聚體形成，這可導(dǎo)致DNA損傷和/或突變[88]，紫外線誘導(dǎo)的膽固醇生物合成對(duì)于SOCE抑制和細(xì)胞的轉(zhuǎn)移至關(guān)重要。Wong等[89]對(duì)黑色素瘤細(xì)胞進(jìn)行單細(xì)胞測(cè)序，發(fā)現(xiàn)STIM1在黑色素瘤中的表達(dá)以細(xì)胞特異性的方式影響細(xì)胞生理。具體來說，惡性細(xì)胞來源的STIM1共表達(dá)基因表達(dá)被抑制，研究首次將黑色素瘤組織中惡性STIM1的表達(dá)與免疫調(diào)節(jié)聯(lián)系起來。STIM1與C-X-C基序趨化因子配體12(C-X-C motif chemokine ligand 12，CXCL12)共表達(dá)，而CXCL12可與CD8+T細(xì)胞、CD4+T調(diào)節(jié)細(xì)胞、CD4+T輔助細(xì)胞、NK細(xì)胞和巨噬細(xì)胞上的趨化因子受體C-X-C基序趨化因子受體4(C-X-C motif chemokine receptor 4，CXCR4)結(jié)合，觸發(fā)下游免疫信號(hào)通路。另外，Sun等[90,91]發(fā)現(xiàn)，STIM1介導(dǎo)的Ca2+振蕩信號(hào)通過激活Src促進(jìn)了侵襲偽足前驅(qū)體的組裝，而Ca2+振蕩的破壞則抑制了侵襲偽足的形成，表明STIM1參與調(diào)控侵襲偽足的蛋白水解活性，驅(qū)動(dòng)黑色素瘤的轉(zhuǎn)移。

與非轉(zhuǎn)移性肺癌組織相比，STIM1在轉(zhuǎn)移性肺癌組織中表達(dá)顯著增加，Wang等[92]在A549細(xì)胞中發(fā)現(xiàn)，沉默可抑制A549細(xì)胞在體內(nèi)的轉(zhuǎn)移。STIM1不僅在癌細(xì)胞中有表達(dá)，在基質(zhì)細(xì)胞當(dāng)中也能檢測(cè)到它的存在，提示STIM1與細(xì)胞狀態(tài)的轉(zhuǎn)化有關(guān)。

在血癌當(dāng)中，Lominy等[93]發(fā)現(xiàn)，缺陷的小鼠體內(nèi)白血病浸潤(rùn)器官的壞死炎癥反應(yīng)顯著減少，且一些與炎癥相關(guān)的信號(hào)通路下調(diào)。研究表明，白血病的引起依賴于異常STIM1介導(dǎo)的Ca2+流入而造成的白血病浸潤(rùn)器官的炎癥。

此外，STIM1在甲狀腺癌[94]、前列腺癌[95,96]、骨肉瘤[97]中均高表達(dá)，并在腫瘤的發(fā)生發(fā)展及浸潤(rùn)轉(zhuǎn)移中發(fā)揮重要作用。

3 STIM1在不同腫瘤中的調(diào)控

STIM1在癌癥進(jìn)展當(dāng)中能夠發(fā)揮不同作用，不僅可以作為核心因子直接參與腫瘤的侵襲或轉(zhuǎn)移，也可以作為調(diào)節(jié)因子對(duì)腫瘤的進(jìn)展進(jìn)行間接調(diào)控。

3.1 STIM1的上游調(diào)控途徑

除了已發(fā)現(xiàn)的SOCE特異調(diào)控劑外，一些生物信號(hào)或通路也參與調(diào)控STIM1的表達(dá)，進(jìn)而影響疾病的發(fā)生。

Ritchie等[98]發(fā)現(xiàn)，腎母細(xì)胞瘤基因1(wilms tumor suppressor 1，WT1)和早期生長(zhǎng)反應(yīng)因子1 (early growth response 1，EGR1)在急性髓系白血病、腎母細(xì)胞瘤、乳腺癌、膠質(zhì)母細(xì)胞瘤和前列腺癌中能夠調(diào)控STIM1表達(dá)；最近，Lee等[99]在乳腺癌當(dāng)中發(fā)現(xiàn)孕酮受體膜組分1 (progesterone receptor membrane component 1，PGRMC1)促進(jìn)SOCE，并作為STIM1的功能相互作用因子，促進(jìn)STIM1構(gòu)象轉(zhuǎn)換，加快腫瘤進(jìn)展；此外，F(xiàn)aris等[100]在轉(zhuǎn)移性結(jié)直腸癌的淋巴細(xì)胞中發(fā)現(xiàn)二酰甘油激酶(diacylglycerol kinase)負(fù)調(diào)控STIM1，干擾SOCE自身強(qiáng)度，以間接影響癌癥進(jìn)展。

另外，microRNA也能實(shí)現(xiàn)對(duì)STIM1的調(diào)控。Zhang等[101]發(fā)現(xiàn)，一種與EMT相關(guān)的miR-185介導(dǎo)的轉(zhuǎn)錄后調(diào)控能夠左右STIM1的水平，miR-185-STIM1軸促進(jìn)結(jié)直腸癌轉(zhuǎn)移。另一種miR-195也被發(fā)現(xiàn)能夠調(diào)控STIM1，并在調(diào)控?fù)p傷后細(xì)胞的遷移中起著重要作用[102]。miR?541?3p被證實(shí)直接調(diào)控STIM1表達(dá)，從而實(shí)現(xiàn)對(duì)細(xì)胞活力和遷移的刺激[103]。與上述幾個(gè)microRNA相反，miR-4725-3p通過直接靶向STIM1的30個(gè)非翻譯區(qū)來抑制膠質(zhì)瘤細(xì)胞的侵襲[104]；miR-223靶向STIM1，抑制乳腺癌生物學(xué)行為[105]。綜上所述，STIM1可以通過miRNA實(shí)現(xiàn)對(duì)癌癥的進(jìn)展的多元化的調(diào)控。

3.2 STIM1參與腫瘤進(jìn)展的下游調(diào)控

STIM1作為介導(dǎo)SOCE的關(guān)鍵因子，在腫瘤的發(fā)生和轉(zhuǎn)移當(dāng)中擔(dān)任核心角色。Wang等[106]發(fā)現(xiàn)，STIM1的異位表達(dá)促進(jìn)了結(jié)直腸癌細(xì)胞的運(yùn)動(dòng)性。STIM1通過增加環(huán)氧合酶-2(cyclooxygenase-2，COX-2)的表達(dá)和前列腺素E2(production of prosta-glandin E2，PGE2)的產(chǎn)生來促進(jìn)結(jié)直腸癌細(xì)胞的遷移。Chen等[107]的研究表明，沉默顯著改變了podosome的動(dòng)態(tài)，縮短了podosome的維持時(shí)間，并減弱了細(xì)胞的侵襲性。在缺失(?/?)小鼠胚胎纖維細(xì)胞中將cDNA進(jìn)行短暫表達(dá)，促進(jìn)了podosome的形成，表明STIM1介導(dǎo)的SOCE激活直接調(diào)控podosome的形成。另有研究表明，下調(diào)STIM1的表達(dá)可顯著抑制細(xì)胞增殖，并使肺癌細(xì)胞周期阻滯在G2/M期和S期[108]。此外，Algariri等[109]在急性髓細(xì)胞白血病-M5細(xì)胞系中通過研究發(fā)現(xiàn)STIM1正調(diào)控NADPH氧化酶-2(NADPH oxidase-2，NOX2)和蛋白激酶C(protein kinase C，PKC)，改變細(xì)胞內(nèi)ROS水平，以影響細(xì)胞內(nèi)環(huán)境。

STIM1除了直接影響腫瘤遷移和相關(guān)進(jìn)展，也能通過改變細(xì)胞骨架或細(xì)胞黏附實(shí)現(xiàn)同樣的目的。Lin等[110]發(fā)現(xiàn)，構(gòu)成型活性的STIM1顯著增加了Ca2+內(nèi)流、鈣蛋白酶活性和FA蛋白的周轉(zhuǎn)，從而阻礙細(xì)胞的遷移；研究表明，癌細(xì)胞需要適量的Ca2+調(diào)節(jié)鈣蛋白酶活性來控制局灶粘連的組裝和拆卸。超載的Ca2+導(dǎo)致異常的鈣蛋白酶活性，不利于癌癥轉(zhuǎn)移。

3.3 STIM1與其他途徑相互作用調(diào)控癌癥進(jìn)展

在STIM1單獨(dú)不能參與調(diào)控癌癥進(jìn)展時(shí)，一些與STIM1相互作用分子或途徑可以幫助其實(shí)現(xiàn)目標(biāo)。Li等[111]發(fā)現(xiàn)，STIM1與缺氧肝癌細(xì)胞中HIF-1α相互作用。HIF-1α直接控制STIM1的轉(zhuǎn)錄，并參與對(duì)SOCE的調(diào)控。在宮頸癌中，表皮生長(zhǎng)因子EGF被發(fā)現(xiàn)可以顯著促進(jìn)STIM1和Orai1在細(xì)胞膜膜旁區(qū)域的相互作用，以誘導(dǎo)Ca2+內(nèi)流[112]。

另外，Sun等[113]在入侵的黑色素瘤細(xì)胞中，觀察了由STIM1-Orai1復(fù)合物介導(dǎo)的鈣瞬變現(xiàn)象。在靜息條件下，鈣瞬變優(yōu)先發(fā)生在單個(gè)侵襲小體和細(xì)胞外周附近的部位。異常的鈣瞬變提供了較高的Ca2+微域以局部激活Ca2+/鈣調(diào)素依賴的Pyk2，從而啟動(dòng)細(xì)胞侵襲所需的SOCE-Pyk2-Src信號(hào)級(jí)聯(lián)。敲除顯著降低了鈣瞬變頻率，降低了整體SOCE水平，減弱了侵襲小體的形成。上述結(jié)果表明，STIM1與Orai1介導(dǎo)的SOCE時(shí)空動(dòng)態(tài)在協(xié)調(diào)侵襲信號(hào)形成等復(fù)雜細(xì)胞行為中具有關(guān)鍵作用。

4 結(jié)語(yǔ)與展望

STIM1在多數(shù)腫瘤中高表達(dá)，通過促侵襲偽足生成、促血管生成、介導(dǎo)炎癥反應(yīng)、改變細(xì)胞骨架和細(xì)胞動(dòng)力等多個(gè)生物進(jìn)程，促進(jìn)腫瘤細(xì)胞向周圍組織浸潤(rùn)及轉(zhuǎn)移。既往研究中有關(guān)靶向STIM1抑制腫瘤進(jìn)展分為以下幾個(gè)方向：STIM1能夠通過Ca2+構(gòu)象的改變以實(shí)現(xiàn)自抑制[114]；也能通過miRNA實(shí)現(xiàn)功能抑制。此外，傳統(tǒng)SOCE的抑制劑可對(duì)STIM1起作用，如羧基胺三唑，可抑制血管生成[115～118]，而2-氨基乙基二苯基硼酸鹽(2-APB)和SKF-96365，都能對(duì)癌細(xì)胞產(chǎn)生類似的作用[119～122]，然而其特異性需要實(shí)驗(yàn)進(jìn)一步來評(píng)估。

除前面綜述的STIM1與腫瘤發(fā)生發(fā)展的相關(guān)分子機(jī)制外，還有許多可供研究的方向與思路：首先，SOCE作為細(xì)胞內(nèi)Ca2+信號(hào)的傳導(dǎo)者之一，對(duì)維持胞內(nèi)鈣信號(hào)穩(wěn)態(tài)至關(guān)重要。鑒于STIM1在SOCE當(dāng)中的重要作用，探究與STIM1相關(guān)信號(hào)調(diào)控通路十分必要。其次，胞外基質(zhì)金屬蛋白酶(matrix metallo-peptidase，MMPs)家族是一類鋅依賴性內(nèi)肽酶，能夠降解大多數(shù)細(xì)胞外基質(zhì)。其成員之一MT1-MMP定位在細(xì)胞膜上，并在多種腫瘤中高表達(dá)[123]。研究發(fā)現(xiàn)SOCE阻斷可能通過抑制MT1-MMP囊泡的質(zhì)膜插入而降低了MT1-MMP的膜表達(dá)[90]，因此研究細(xì)胞外基質(zhì)重構(gòu)與STIM1/SOCE信號(hào)間聯(lián)系也具有重要意義。另外，自噬調(diào)控失調(diào)和腫瘤的發(fā)生發(fā)展密切相關(guān)，Ca2+在基礎(chǔ)自噬和誘導(dǎo)自噬中起著重要的作用。研究STIM1在自噬介導(dǎo)的腫瘤發(fā)生發(fā)展中的作用將會(huì)為腫瘤的治療提供策略和靶點(diǎn)[124]。

鑒于STIM1在多種腫瘤高表達(dá)并促進(jìn)腫瘤的惡化，開發(fā)SOCE抑制劑，靶向STIM1的治療將會(huì)為腫瘤治療提供新的方向。

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The roles and mechanism of STIM1 in tumorigenesis and metastasis

Chenghao Yan1, Weiyu Bai1, Zhimeng Zhang1, Junling Shen1, Youjun Wang2, Jianwei Sun1

STIM1 (stromal interaction molecule 1) is one of the key components of the store operated Ca2+entry channel (SOCE), which is located on the endoplasmic reticulum membrane and highly expressed in most kinds of tumors. STIM1 promotes tumorigenesis and metastasis by modulating the formation of invadopodia, promoting angiogenesis, mediating inflammatory response, altering the cytoskeleton and cell dynamics. However, the roles and mechanism of STIM1 in different tumors have not been fully elucidated. In this review, we summarize the latest progress and mechanisms of STIM1 in tumorigenesis and metastasis, thereby providing insights and references for the study on STIM1 in the field of cancer biology in the future.

STIM1; SOCE; tumorigenesis; metastasis

2023-02-18;

2023-04-03;

2023-04-17

國(guó)家自然科學(xué)基金項(xiàng)目(編號(hào): 82273460，32260167)和云南大學(xué)研究生科研創(chuàng)新項(xiàng)目(編號(hào): 2021Z088，2023Y0222)資助[Supported by the National Natural Science Foundation of China (Nos. 82273460，32260167)，and Yunnan University Graduate Research Innovation Project (Nos. 2021Z088, 2023Y0222)]

嚴(yán)程浩，在讀碩士研究生，專業(yè)方向：腫瘤轉(zhuǎn)移與發(fā)生機(jī)制。E-mail: ych9702@126.com

白韋鈺，在讀博士研究生，專業(yè)方向：腫瘤轉(zhuǎn)移與發(fā)生機(jī)制。E-mail: weiyubai@mail.ynu.edu.cn

嚴(yán)程浩和白韋鈺并列第一作者。

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

王友軍，博士，研究方向：鈣信號(hào)轉(zhuǎn)導(dǎo)機(jī)制及其生理病理作用。E-mail: wyoujun@bnu.edu.cn

10.16288/j.yczz.23-035

(責(zé)任編委: 宋旭)