Advances of Endoplasmic Reticulum Stress/Unfolded Protein Response Promote Tumor Invasion
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摘要:
内质网应激/未折叠蛋白反应促进肿瘤侵袭是肿瘤调控的新机制,适度的内质网应激不仅可以保护细胞还能促进肿瘤细胞侵袭。许多研究表明内质网应激/未折叠蛋白反应与肿瘤的发生发展密切相关,且能通过上调血管内皮生长因子、葡萄糖调节蛋白78、前梯度蛋白2的表达、促进上皮间质转化、降解细胞外基质等方式促进肿瘤侵袭,了解内质网应激/未折叠蛋白反应与肿瘤侵袭性之间的关系可能为肿瘤治疗提供新方向。本文将对内质网应激/未折叠蛋白反应促进肿瘤侵袭的相关机制作一综述。
Abstract:Endoplasmic reticulum stress/unfolded protein response is a new regulatory mechanism that promote tumor invasion. Moderate endoplasmic reticulum stress can not only protect the cells but also promote cell invasive. Many studies have shown that endoplasmic reticulum stress/unfolded proteins response is closely related to the development of tumor and can promote tumor invasion through regulate the expression of the Vascular endothelial growth factor (VEGF), glucose-regulated protein78(GRP78), anterior gradient 2(AGR2), promote the transformation of epithelial mesenchymal and degrade extracellular matrix. Understand the links between endoplasmic reticulum stress/unfolded protein response and tumor invasion may provide a new direction for tumor treatment. In this article, we will review summarize the current knowledge about the relevant mechanism of endoplasmic reticulum stress/unfolded proteins response promote tumor invasion.
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Key words:
- Endoplasmic reticulum stress /
- Invasion /
- VEGF /
- Epithelial-mesenchymal transition /
- GRP78 /
- AGR 2 /
- Extracellular matrix
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0 引言
肿瘤细胞普遍存活于缺血低氧微环境中,导致内质网内未折叠蛋白或错误折叠蛋白聚积,引起内质网应激(endoplasmic reticulum stress, ERS),为适应应激微环境,细胞激活未折叠蛋白反应(unfolded protein response, UPR),恢复内质网稳态[1]。
内质网上有三个跨膜蛋白即双链RNA激活的蛋白激酶样内质网激酶(PKR like ER kinase, PERK)、需肌醇酶1(type-Ⅰ endoplasmic reticulum transmembrane protein kinase, IRE1)和活化转录因子6(activating transcription factor 6, ATF6),分别对应UPR下游三条信号通路。正常状态下,PERK、IRE1和ATF6与葡萄糖调节蛋白78(glucose-regulated protein78, GRP78)结合失活,ERS时未折叠或错误折叠蛋白与GRP78结合,使GRP78从PERK、IRE1和ATF6上解离,激活UPR。PERK激活后可抑制翻译起始因子-2的α亚基 (eukaryotic translation initiation factor-2 alpha subunit, eIF2α),抑制蛋白质合成,上调ATF4、增强子结合蛋白同源蛋白(enhancer-binding protein homologous protein, CHOP)等凋亡蛋白,诱导细胞凋亡。激活的IRE1可使X-盒结合蛋白1(X-box binding protein 1, XBP1)剪切激活,后者与ERS反应原件结合诱导GRP78、CHOP及内质网甘露糖苷酶样蛋白等表达,增加错误折叠蛋白的降解,促进内质网功能的恢复;此外还能激活c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)通路及其特有的Caspase-12凋亡通路促进细胞凋亡。解离的ATF6向高尔基体转位,被核内切酶片段1和核内切酶片段2剪切激活后进入细胞核内,激活的ATF6可以上调与蛋白质和脂类合成相关的内质网基因的表达。
侵袭性是肿瘤最主要的生物学特性之一,为手术根治带来了巨大的困难,也是肿瘤复发、致死的主要原因之一。肿瘤侵袭是一个复杂的多步骤连续的过程,受多种因子调控,如Rb基因、表皮生长因子等[2-3]。最近研究发现ERS/UPR不仅与肿瘤存活、凋亡有关,还能通过以下多种方式影响肿瘤侵袭性。
1 通过调节血管生成增强肿瘤细胞的侵袭性
血管内皮生长因子(vascular endothelial growth factor, VEGF)是人体血管生成过程中重要的调控因子,在诱导血管发生和血管生成及内皮细胞生长、促进细胞迁移等方面发挥重要作用。靶向VEGF治疗肿瘤已成为近年来研究的热点。
为适应缺血低氧微环境,肿瘤主要依靠缺氧诱导因子1α(hypoxia inducible factor-1, HIF-1α)上调VEGF表达,促进血管生成提高氧供[4]。近年来许多研究表明ERS/UPR可以通过调节VEGF表达诱导肿瘤血管生成,促进肿瘤细胞侵袭迁移。Pereira等研究显示,肿瘤细胞中激活的ATF4和XBP1可以与VEGF启动子结合促进其表达,而与HIF-1α同时激活时,ATF与HIF-1α形成复合体加强HIF-1α对VEGF的转录调控[5]。同样Chen等发现在三阴乳腺癌细胞中XBP1可以通过HIF-1α途径或与HIF-1α协同调节VEGF的表达,促进肿瘤的侵袭影响患者预后[6]。Jamison等研究发现,在髓母细胞瘤中适宜的PERK-eIF2a激活可以通过增强VEGF-A/VEGFR2信号促进肿瘤侵袭迁移[7]。Wang等发现,在人类肿瘤细胞中,低糖诱导的ERS/UPR能上调VEGF等的表达,促进肿瘤侵袭,沉默PERK减少了VEGF等的表达,暗示PERK/ATF4通路可通过调节VEGF表达调控肿瘤的侵袭性[8]。Ghosh等研究显示在胚胎滋养层细胞中,ERS可以通过IRE1a-XBP-1, PERK-ATF4和ATF6a三条通路促进VEGF的转录激活,不依赖HIF-1a促进血管生成[9]。
最近的研究表明ERS状态下的肿瘤细胞不仅能通过激活UPR通路维持内质网稳态,同时还能通过PERK、ATF6、IRE1a三条途径调控VEGF的表达,影响肿瘤的侵袭迁移,对肿瘤转移起了重要作用。以ERS/UPR调控的VEGF通路为靶点治疗肿瘤可能成为新的治疗手段。
2 通过上皮间质转化促进肿瘤细胞侵袭
上皮间质转化(epithelial-mesenchymal transition, EMT)是指上皮细胞通过特定程序转化为具有间质表型细胞的生物学过程。在胚胎发育、组织重建、癌症转移等过程中有重要作用,主要的特征为E-钙黏蛋白表达的减少、细胞骨架转化为波形蛋白为主。阐明调控癌症细胞发生EMT过程的分子机制及其在癌症发生、发展中的作用对抗癌治疗有重要意义。
之前的研究揭示了肿瘤EMT被一组锌指转录因子如snail家族 (snail and slug),Zeb1和Twist通过WNT、IL-6、Notch等通路调控[10-11],如胰腺癌中通过WNT和Notch通路可以促进EMT从而促进肿瘤侵袭转移过程[12]。最近许多研究指出肿瘤细胞ERS/UPR可以通过多种方式促进EMT,增加肿瘤的侵袭转移能力,但具体机制没有完全明了。Li等研究发现,在乳腺癌细胞中XBP1通过调节snail的表达促进EMT,提高肿瘤的侵袭能力,沉默XBP1或Snail抑制了EMT导致的肿瘤侵袭,暗示XBP1/Snail作为新奇的通路有助于乳腺癌的侵袭和转移[13]。ER蛋白29(endoplasmic reticulum protein, ERp29)属于内质网蛋白质,高表达的ERp29通过下调Twist、Slug,活化E-钙黏蛋白,降解纤黏蛋白等促进EMT,降低了细胞侵袭迁移的能力,在乳腺癌细胞中XBP1通路的激活抑制了ERp29表达,抑制了EMT从而增加了肿瘤侵袭能力[14-15]。Shah等发现,在肺腺癌细胞中p97缺失可导致ERS,后者激活蛋白激酶B(Protein kinase B, AKT)和Src酪氨酸激酶,促进EMT及肿瘤侵袭转移,抑制AKT或Src阻碍了ERS诱导的EMT及肿瘤侵袭迁移[16]。此外在其他疾病中ERS/UPR也能影响EMT。Tanjore等发现,在肺泡上皮细胞中ERS通过Smad和Src激酶两条途径刺激细胞EMT,其过程部分依赖IRE-1的调控[17];Shin等发现在腹膜间皮细胞中ERS通过激活Smad2/3通路促进了Snail和b-连环蛋白表达从而促进了EMT,也可以通过调节转化生长因子-β1(transforming growth factor-β1, TGF-β1)促进EMT[18]。
EMT是恶性肿瘤细胞迁移和侵袭的重要步骤,处于应激状态下的肿瘤细胞能够通过EMT改变自身表型来适应或降低ERS,进而提高自身生存能力。最近Feng等研究发现,在TGF-β诱导的EMT的癌症细胞中,EMT通过激活PERK-eIFa通路促进了细胞侵袭,抑制PERK降低了EMT的癌细胞的侵袭转移能力[19]。肿瘤细胞中ERS/UPR和EMT相互影响促进肿瘤细胞适应微环境,增加了肿瘤的侵袭转移,探索两者之间的联系对肿瘤发生、发展及转移至关重要,靶向两者之间的关键因子可能成为肿瘤治疗的关键。
3 高表达GRP78促进肿瘤细胞侵袭
GRP78是内质网合成分泌的蛋白质,属于热休克蛋白70家族,作为内质网分子伴侣蛋白,其参与内质网中蛋白质的折叠和转运,对维持内质网稳态起了重要作用,此外还可以转运至细胞质、细胞膜甚至分泌到细胞外,参与调控细胞分化、存活、转移等重要的生物学过程。
GRP78作为内质网分子伴侣,在ERS时表达被上调。研究表明GRP78在结肠癌、食管癌、胰腺癌、肝癌等多种癌症中高表达,且高表达的GRP78与肿瘤侵袭转移有关[20]。Yuan等研究显示,在胰腺癌中高表达的GRP78激活黏着斑激酶(focal adhesion kinase, FAK)及JNK通路,促进了基质金属蛋白酶(matrix metalloproteinases, MMPs)的表达及肿瘤侵袭和转移,敲掉GRP78抑制了JNK的磷酸化、降低了MMPs的表达,且激活了RhoA通路,通过诱导应力纤维形成抑制了肿瘤的侵袭能力[21]。Li等研究发现,结肠癌中GRP78可以通过B-连环蛋白上调尿激酶型纤溶酶原激活物(uPA)的表达,并与uPA相互影响,促进两者的分泌提高了肿瘤的侵袭能力[22]。Zhao等发现,肝癌细胞表面GRP78能和α2M相互作用促进c-Src的磷酸化,后者能激活表皮生长因子受体,从而促进了肿瘤细胞侵袭和转移[23]。此外,在黑色素瘤细胞中GRP78高表达且对肿瘤的侵袭转移有直接的促进作用,敲掉GRP78则抑制了肿瘤的侵袭转移能力[24]。也有研究发现,敲掉GRP78可通过抑制PI3K/Akt信号通路, 显著降低肿瘤细胞的转移能力[25]。
ERS状态下,肿瘤细胞高度表达GRP78,通过调节MMPs表达、促进EMT及多种通路刺激了肿瘤细胞侵袭及转移。但也有研究表明GRP78低表达促进了肿瘤侵袭转移,如在结肠癌细胞中沉默GRP78能够减少E-钙黏蛋白的表达,促进EMT,同时激活核转录因子E2相关因子2/血红素加氧酶-1(nuclear factor erythroid-2 related factor 2/heme oxygenase-1, NRF-2/HO-1)通路,促进了肿瘤侵袭转移[26]。GRP78作为人体内重要的功能蛋白,尽管其在不同肿瘤组织中的功能各异,但以GRP78为靶点治疗肿瘤将有美好的前景,可能为肿瘤治疗指明新的方向。
4 高表达AGR2促进肿瘤细胞侵袭
前梯度蛋白2(anterior gradient 2, AGR2)是近年来发现的蛋白二硫键异构酶家族成员蛋白,UPR下游效应分子,它们定位在细胞内质网,在ERS中起着重要作用,参与调控蛋白质折叠、成熟和分泌等过程,促进肿瘤发生发展。ERS状态下,ARG2的表达显著升高,促进肿瘤生长、增加对氧化应激的抵抗性、维持内质网的稳态。
许多研究表明,ARG2在乳腺癌、肺癌、胰腺癌、胃癌等多种癌症中高表达,且与肿瘤的转移表型和不良预后相关,如低氧环境下培养的ERS状态的乳腺癌细胞中AGR2 mRNA增高5倍,ARG2高表达参与肿瘤的迁移与侵袭[27]。Di等发现,在人甲状腺乳头状癌细胞中,异常增加的ARG2促进了肿瘤细胞的迁移侵袭,敲掉ARG2基因后降低了肿瘤细胞的迁移侵袭性[28]。Tsuji等研究显示,在人胃印戒细胞癌中,ARG2高表达且可以通过旁分泌途径激活周围基质纤维母细胞,两者联合促进胃癌细胞迁移侵袭[29]。Zhang等研究发现,高表达的ARG2与胃癌的位置、浸润深度及TNM分期有关,且作为独立的预后因子其能通过促进组织蛋白酶D表达共同影响肿瘤的迁移侵袭及预后[30]。
此外ARG2可以促进肝癌细胞的增殖及侵袭、增加乳腺癌细胞的黏附从而增加其迁移侵袭的能力、调节人头颈部鳞癌细胞EMT过程、增加肿瘤侵袭转移能力[31]。ERS状态下的肿瘤细胞ARG2表达增高,促进了肿瘤的侵袭和转移,抑制ARG2减弱了肿瘤的侵袭性且增加了ERS诱导的细胞凋亡,暗示着抑制ARG2的表达可能成为肿瘤治疗的新靶点。
5 通过降解细胞外基质促进肿瘤细胞侵袭转移
细胞外基质(extracellular matrixc, ECM)是细胞合成并分泌到细胞表面或细胞之间的大分子,主要是一些多糖、蛋白或蛋白聚糖。这些物质构成复杂的网架结构,支持并连接组织结构、调节组织的发生和细胞的生理活动。恶性肿瘤的发生、发展、侵袭和转移常常伴有ECM的变化,合成及分泌大量基质降解酶降解ECM是肿瘤细胞侵袭转移的重要步骤。
MMPs是一组结构上具有极大同源性、能够降解细胞外基质蛋白的内肽酶。近年研究发现,细胞外基质降解是肿瘤侵袭和转移的关键环节,MMPs可通过调节细胞外基质影响肿瘤细胞的侵袭和扩散。Sanda等发现,由氧化低密度脂蛋白诱导的ERS可促进MMP-9的表达和分泌[32];董凯楠等研究显示在胃癌细胞中,依霉素诱导的ERS可显著上调MMP-9的表达,后者通过降解细胞外基质增强胃癌细胞向外侵袭的能力[33]。Zhao等发现,在高度转移的食管鳞状细胞癌中,MMP-2及MMP-9高表达与GRP78表达正相关,抑制GRP78水平降低了MMP-2、MMP-9的表达,从而限制了肿瘤的侵袭能力[34]。
溶酶体膜相关蛋白(lysosome-associated membrane proteins, LAMPs)是参与细胞溶酶体形成及维持细胞溶酶体稳定的关键膜蛋白,细胞癌变过程中,大量组织蛋白酶被分泌到胞质,与MMPs等共同参与细胞外基质的降解,提高了肿瘤细胞的侵袭转移。目前已在食管癌、大肠癌、输卵管癌、卵巢癌、乳腺癌以及肝癌中均发现LAMP高表达。Nagelkerke等研究发现乳腺癌中LAMP3的表达与缺氧微环密切相关[35],其机制可能为缺氧微环境通过PERK/eIF2α/ATF4通路而不是HIF-1α通路上调LAMP3的表达,从而增强癌细胞向远处转移的侵袭能力[36]。Nagelkerke等还发现,在人类头颈部鳞状细胞癌中,低氧诱导PERK/ATF4/LAMP3高度激活影响患者预后,可能与LAMP3高表达增加了癌症侵袭性有关[37]。
6 通过其他机制促进肿瘤细胞侵袭转移
半胱氨酸酸性蛋白(secreted protein, acidic and rich in cyst-eine, SPARC)是一种具有多个功能的小分子酸性蛋白,其主要作用是抗细胞黏附、促进细胞骨架重排、提高MMPs表达,对ECM的降解有促进作用。研究发现,在胶质瘤U87细胞中,激活的IRE1可促进SPARC的mRNA表达进而刺激了肿瘤侵袭[38];Li等研究发现,在乳腺癌中抑制ERS诱导的乙酰肝素酶的表达可显著降低肿瘤的侵袭转移能力[39];Wu等发现,胃癌细胞中ERP19高度表达,且对肿瘤的侵袭转移起到了促进作用,敲除ERP19后其侵袭转移能力明显减弱[40],其机制可能是激活了FAK/桩蛋白通路[41]。
7 结语
近年来发现ERS/UPR不仅能维持内质网稳态、对抗细胞氧化应激,还能通过多种方式促进肿瘤侵袭转移,为肿瘤的生存提供新的保障。ERS/UPR与肿瘤侵袭性关系密切、复杂,具体互联机制尚未完全明了,明确其间的关系可能对肿瘤的治疗提供新的思路。
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