PI3K/AKT/mTOR信号通路在EMT发生发展过程中的研究进展
Research Progress of PI3K/AKT/mTOR Signaling Pathway in the Occurrence and Development of EMT
DOI: 10.12677/acm.2024.1441384, PDF, HTML, XML, 下载: 38  浏览: 63 
作者: 张 瑜, 翟笑妍：内蒙古医科大学护理学院，内蒙古 呼和浩特；解文浩*：内蒙古医科大学附属医院，内蒙古 呼和浩特
关键词: 磷脂酰肌醇3激酶、上皮细胞–间充质转化；肿瘤；Phosphatidylinositol 3 Kinase； Epithelial-Mesenchymal Transformation； Tumor
摘要: 上皮细胞–间充质转化(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。癌细胞中的部分EMT被认为可以增强其侵袭特性，并促进对抗癌药物的耐药性。磷脂酰肌醇3激酶/蛋白激酶B/哺乳动物雷帕霉素蛋白(PI3K/AKT/mTOR)信号转导通路在恶性肿瘤细胞的增殖、凋亡、侵袭、转移和血管新生方面起着重要作用。在肿瘤的发生发展过程中PI3K/AKT/mTOR信号通路的激活是导致肿瘤细胞生长、发展、增殖、转移特别是EMT失调的重要原因。本文主要针对细胞EMT与PI3K/AKT/mTOR信号转导通路之间的关系进行综述。
Abstract: Epithelial-mesenchymal transformation (EMT) refers to the biological process by which epithelial cells are transformed into cells with interstitial phenotypes through a specific procedure. Partial EMTs in cancer cells are thought to enhance their aggressive properties and promote resistance to anti-cancer drugs. Phosphatidylinositol 3 kinase/protein kinase B/mammalian rapamycin protein (PI3K/AKT/mTOR) signal transduction pathway plays an important role in the proliferation, apoptosis, invasion, metastasis and angiogenesis of malignant tumor cells. The activation of PI3K/AKT/ mTOR signaling pathway is an important reason for the growth, development, proliferation and metastasis of tumor cells, especially the disorder of EMT. This review focuses on the relationship between cellular EMT and PI3K/AKT/mTOR signal transduction pathways.
文章引用：张瑜, 解文浩, 翟笑妍. PI3K/AKT/mTOR信号通路在EMT发生发展过程中的研究进展[J]. 临床医学进展, 2024, 14(4): 3005-3011. https://doi.org/10.12677/acm.2024.1441384

1. 上皮细胞–间充质转化

1.1. EMT的概念

上皮细胞–间充质转化(EMT)是指上皮细胞通过特定的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、慢性炎症和多种纤维化疾病中发挥了重要作用。其主要的特征是细胞角蛋白细胞骨架转化为波形蛋白(Vimentin)为主的细胞骨架、细胞黏附分子(如E-钙黏蛋白，Ecadherin)表达的减少及形态上具有间充质细胞的特征等 [1] 。

1.2. EMT的功能

正常的上皮细胞通过侧细胞连接(紧密连接、粘附连接、间隙连接和桥粒)连接在一起。EMT使上皮细胞失去细胞极性，失去与基底膜的连接等上皮表型，获得了较高的迁移与侵袭、抗凋亡和降解细胞外基质的能力等间质表型。

1.3. EMT的分型

根据EMT发生的特定生物学环境可以分为3型。I型EMT：与胚胎植入、发育和器官形成有关。II型EMT：与损伤修复、组织再生和器官纤维化相关。III型EMT：是指与上皮细胞恶性肿瘤相关的表型转化。原发性上皮组织肿瘤细胞通过III型EMT形成具有迁移能力的间充质细胞，随血流转移至不同部位形成上皮细胞的肿瘤转移灶。与I型和II型EMT所形成的完全丧失上皮细胞表型的间充质细胞不同的是，III型EMT形成的转移性肿瘤细胞在获得间充质表型的同时保持一定的上皮细胞的特性。

2. PI3K/AKT/mTOR通路

2.1. PI3K/AKT/mTOR通路的组成

PI3K/AKT/mTOR信号通路主要由PI3K (磷脂酰肌醇3激酶)、AKT (蛋白激酶B)和Mtor (哺乳动物雷帕霉素蛋白)组成。该通路在恶性肿瘤细胞的发生、发展、转移和血管新生等方面发挥着重要作用。

2.2. PI3K

PI3K可分为I、II、III型，在这些激酶中，研究最广泛的是I型，它可以直接被细胞表面受体激活。根据其激活模式I类PI3K又可以进一步分为IA和IB类。IA类PI3K由RTK、G蛋白偶联受体和小G蛋白RAS激活。IB类PI3Ks仅由一个亚基(PI3Kγ)组成，由G蛋白偶联受体激活。其中IA型PI3K在癌症中发挥更重要的作用 [1] 。

2.3. AKT

AKT也被称为蛋白激酶B(PKB)是PI3K信号通路下游的重要成员，包括三个亚型：AKT1、AKT2和AKT3，分别由PKBα、PKBβ和PKBγ编码。该酶是一种丝氨酸/苏氨酸激酶，由N-末端PH结构域、中央激酶结构域CAT和含有调节疏水基序的C-末端EXT域组成。PH结构域的主要功能是调节蛋白质–蛋白质、蛋白质–脂质间的相互作用，CAT域主要负责酶的活性并与蛋白激酶A(PKA)和蛋白激酶C(PKC)具有高度同源性，AKT的激活有赖于该结构域中的Thr308的磷酸化。

2.4. mTOR

mTOR是PI3K相关激酶蛋白家族的成员，具有丝/苏氨酸蛋白激酶活性，参与并调节细胞的生长和增殖 [2] 。mTOR包括mTOR复合物1 (mTORC1)和mTOR复合物2 (mTORC2)，它们接受着不同的调控，也有不同的作用。mTORC1对雷帕霉素敏感，由mTOR、Raptor和mLST8组成，主要在细胞生长和能量代谢等方面发挥作用。mTORC2对雷帕霉素不敏感，由mTOR、Rictor、Sin1和mLST1组成，在细胞生长增殖和细胞骨架的重塑等方面发挥作用。

3. EMT与PI3K/AKT/mTOR的关系

EMT对癌症的发展至关重要 [3] 。EMT期间细胞失去上皮特征并获得间充质特征,EMT的标志是上皮标志物E-钙粘蛋白的缺失和间充质标志物Vimentin的升高 [4] 。PI3K信号通路在细胞周期、代谢和运动中起重要作用。下面的一些研究表明PI3K/AKT/mTOR信号通路的激活在肿瘤细胞的发生发展过程中尤其是在肿瘤细胞生长、发展、增殖、转移特别是EMT失调的重要原因。现在已经有研究通过PI3K/AKT信号通路介导的EMT过程来干预肿瘤的转移，成为干预肿瘤转移的靶点。

PI3K是一种脂质激酶，可将PIP2转化为PIP3，后者可以使AKT易位到质膜，在质膜上被PDK1和PDK2磷酸化并激活 [5] 。AKT作为PI3K/AKT/mTOR信号传导的关键组成部分，可以通过调节RB高磷酸化和失活来抑制GSK3诱导细胞周期进展，并通过磷酸化使促凋亡因子Bad和procaspase-9失活以调节细胞凋亡 [6] 。还可以通过EMT转录因子(Snail和Twist)抑制E-cad来介导EMT [7] 。由活化的AKT驱动的EMT涉及细胞–细胞粘附力的丧失，形态的改变，细胞极化的丧失以及诱导细胞的运动。mTOR是PI3K/AKT/mTOR通路中的关键蛋白之一。AKT的激活可以通过抑制结节性硬化症复合物(TSC)在丝氨酸残基939处的磷酸化和14-3-3蛋白的结合，从而促进mTOR活性，mTOR络合物作为PI3K-AKT信号通路的关键下游靶标，也通过直接激活AKT来调节EMT [8] 。

很多研究结果已经证实多种因素可以通过PI3K/AKT通路在EMT中发挥重要的作用，如磷酸酶和张力蛋白同源物(PTEN)是一种肿瘤抑制因子，该因子的突变常在很多癌症的发生中出现。F-box蛋白11通过抑制PTEN水平进而激活PI3K/AKT信号通路来促进胃癌的生长，EMT和转移 [9] 。NR2F2-AS1下调使PTEN表达上调降低了鼻咽癌细胞的增殖并增加了细胞凋亡 [10] 。还有研究表明Pleckstrin同源性样域家族A成员2 (PHLDA2)的低表达会部分降低PI3K，p-AKT的表达，并增加GSK3β的表达 [11] 。β-连环蛋白是EMT的重要调节因子，GSK3β的磷酸化能够抑制T-β-连环蛋白和N-β-连环蛋白的表达 [12] 。PHLDA2的低表达可以通过PI3K/AKT/mTOR和PI3K/AKT/GSK3β通路诱导结直肠癌细胞的EMT，从而抑制结直肠癌细胞的增殖同时通过EMT抑制结直肠癌细胞的侵袭和转移 [11] 。其中PHLDA2通过PI3K/AKT途径还可以抑制胃癌细胞的凋亡，与胃癌的发生有关 [13] 。PHLDA2可以通过PI3K/AKT/mTOR通路来降低骨肉瘤患者的发生和转移 [14] 。近期的一项研究表明GP5基因高表达于乳腺癌组织中,在乳腺癌中可能起到促癌基因的作用，与Her-2表达负相关,而与组织学分级、TNM分期呈正相关，GP5基因可能通过PI3K/AKT信号通路上调EMT促进乳腺癌细胞的增殖、侵袭以及转移 [15] 。近期一项研究表明丝氨酸蛋白酶抑制因子(SERPINDs)家族的成员SERPIND1在卵巢上皮性恶性肿瘤组织中高表达表达，该蛋白可以激活PI3K/AKT信号通路促使其磷酸化,从而促进卵巢癌细胞从G1期向S期的转化,并促进卵巢癌细胞的增殖、迁移、侵袭和EMT并抑制凋亡 [16] 。哺乳动物中鉴定的FAT蛋白家族(FAT1-4)的家族成员FAT肿瘤抑制因子同源物4(FAT4)在抑制上皮间充质EMT和胃癌细胞增殖方面起着重要作用 [17] 。近期研究表明FAT4可以通过PI3K/AKT/mTOR和PI3K/AKT/GSK-3β信号通路抑制EMT并通过调节PI3K的活性以促进自噬 [12] 。有研究表明TREM2可以通过PI3K/AKT信号通路影响EMT，TREM2的表达的降低能够抑制胃癌细胞的增殖，迁移和侵袭，且体内肺转移的发生减少 [18] 。Kim等人证明TREM2通过Wnt1/β-连环蛋白和Erk信号通路来抑制体内和体外肿瘤细胞的发展，并且可以作为结直肠癌的治疗靶点 [19] 。TREM2通过PI3K/AKT/β-连环蛋白信号通路与肝细胞癌的发生有关 [20] 。14,15-EET可以上调整合素αvβ3表达并导致FAK/PI3K/AKT信号通路的激活。并且可以通过整合素αvβ3及其下游FAK/PI3K/AKT/信号传导诱导乳腺癌细胞EMT和顺铂耐药性 [21] 。近期研究表明载脂蛋白C2 (APOC2)在调节富含甘油三酯的脂蛋白(TRL)中至关重要，CD36是一种多配体B类清道夫受体，在脂质代谢中起作用，并参与各种细胞过程 [22] 。在胃癌(GC)细胞中，脂肪酸可以上调CD36表达以触发上皮到间充质转化(EMT)过程，从而促进肿瘤生长和网膜转移 [23] [24] 。CD36还可以通过激活PI3K/AKT信号传导来促进癌症进展 [25] 。最近的一项研究证明CD36和APOC2之间的相互作用通过PI3K/AKT/mTOR信号通路的激活在调节GC细胞的EMT中发挥至关重要的作用，最终促进GC的进展和腹膜转移(PM) [26] 。近期的一项研究表明A-激酶相互作用蛋白1 (AKIP1)通过PI3K/Akt/IKKβ途径激活NF-κB信号传导来促进宫颈癌细胞(CC)中的EMT和转移，这表明AKIP1是CC中EMT轴的关键调节因子 [27] 。羧肽酶A4 (CPA4)是一种新型肿瘤生物标志物，在许多癌症中普遍表达。CPA4可以激活PI3K-AKT-mTOR通路，使PI3K (Tyr458)，AKT (Ser473)和mTOR (Ser2448)的磷酸化，随后诱导EMT增强了细胞的迁移率，并通过减弱细胞凋亡信号传导(Bcl2/Bax和caspase3)促进了耐药性 [28] 。在先前的研究中，肝癌的分级，侵袭，临床分期和预后不良可能与CPA4的高表达有关 [29] 。在食管鳞状细胞癌中，CPA4高表达可以作为独立的预后指标，并且与组织学分级、淋巴结转移和TNM分期密切相关 [30] 。小鼠成虫雪旺细胞衍生的CXCL5可激活PI3K/AKT通路并通过EMT-TF (Snail、Twist)促进肺癌中的EMT [31] 。lnc RNA PTTG3P可以通过上调PTTG1来激活PI3K/AKT信号传导，进而影响细胞周期进展，影响细胞凋亡和EMT [32] 。

4. EMT与肿瘤治疗/耐药

EMT被认为会导致肿瘤转移并引起治疗耐药性。因此，EMT通路在癌症治疗中具有很大的治疗意义，并且可以靶向预防高风险转移性病变患者的肿瘤扩散。相关研究表明，几种药物可以通过调节PTEN来抑制增殖并诱导恶性肿瘤的凋亡,PTEN敲低部分削弱了黄芩素对胃癌细胞的增殖抑制和凋亡促进功能。因此，黄芩素可以通过PTEN途径依赖性地减弱胃癌的生长 [33] 。PTEN基因表达下调、细胞EMT转化及血管生成拟态(VM)形成是胰腺癌细胞产生吉西他滨耐受、放疗抵抗的重要原因 [34] 。Shikonin通过调节miR-106b/PTEN/AKT/mTOR信号通路抑制子宫内膜样子宫内膜癌的发展 [35] 。高良姜素通过抑制microRNA-21表达在胆管癌中具有抗肿瘤作用 [36] 。近期的一项研究表明：LACTB可以调节PIK3R3水平以促进自噬并抑制EMT和增殖，这些效果部分通过PI3K/AKT/mTOR信号通路来实现 [37] 。阿卡西汀(5,7-二羟基-4'-甲氧基黄酮)是一种广泛存在于各种植物中的黄酮，如黑刺槐，异叶假蝗，菊花和广藿香。相关研究表明阿卡西汀通过抑制了PI3K和Akt的磷酸化从而降低了PI3K和Akt的表达来阻断TGF-β1诱导的胃癌细胞EMT，抑制胃癌细胞的腹膜转移和肝转移 [38] 。在乳腺癌细胞中，阿卡西汀被证明以浓度依赖性方式抑制细胞粘附，局灶性粘附形成和迁移 [39] 。黄芩苷是一种生物活性类黄酮，具有抗炎和抗癌活性。其通过抑制EMT和PI3K/Akt/NF-κB途径减弱细胞凋亡，逆转了人A549肺腺癌细胞对顺铂的抗性 [40] 。miR-22可以直接与NLRP3 mRNA的3'-UTR结合抑制PI3K/AKT信号通路来破坏细胞活力和EMT，抑制卵巢癌的PI3K/AKT信号通路 [41] 。小檗碱(BBR)是一种来自Coptis的天然生物碱，具有抗癌活性。研究表明，BBR可以有效抵抗癌细胞的侵袭，对正常细胞无毒性作用，通过抑制EMT抑制结肠癌的侵袭和迁移 [42] 。

5. 展望

综上所述，PI3K/AKT/mTOR信号通路在细胞EMT发展过程中所发挥毋庸置疑的作用，EMT与肿瘤细胞转移、耐药等有关，关于EMT的抑制治疗仍无显著进展，故研究该通路的靶向治疗对于阻断甚至逆转EMT是一个新的机遇。因此，对PI3K/AKT/mTOR信号通路进行分子靶向治疗进一步研究是很有必要的。

NOTES

*通讯作者。

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