ABSTRACT

Autophagy is a highly conserved catabolic process and a major cellular pathway for the degradation of long-lived proteins and cytoplasmic organelles. An increasing body of evidence has unveiled autophagy as an indispensable biological function that helps to maintain normal tissue homeostasis and metabolic fitness that can also lead to severe consequences for the normal cellular functioning when altered. Recent accumulating data point to autophagy as a key player in a wide variety of physiological and pathophysiological conditions in the human endometrium, one of the most proficient self-regenerating tissues in the human body and an instrumental player in placental species reproductive function. The current review highlights the most recent findings regarding the process of autophagy in the normal and cancerous endometrial tissue. Current research efforts aiming to therapeutically exploit autophagy and the methodological approaches used are discussed.

Abbreviations: 3-MA: 3-methyladenine; ACACA (acetyl-CoA carboxylase alpha); AICAR: 5-aminoimidazole-4-carboximide riboside; AKT: AKT serine/threonine kinase; AMPK: AMP-activated protein kinase; ATG: autophagy related; ATG12: autophagy related 12; ATG16L1: autophagy related 16 like 1; ATG3: autophagy related 3; ATG4C: autophagy related 4C cysteine peptidase; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG9: autophagy related 9; Baf A1: bafilomycin A₁; BAX: BCL2 associated X, apoptosis regulator; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; CACNA1D: calcium voltage-gated channel subunit alpha1 D; CASP3: caspase 3; CASP7: caspase 7; CASP8: caspase 8; CASP9: caspase 9; CD44: CD44 molecule (Indian blood group); CDH1: cadherin 1; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; CMA: chaperone-mediated autophagy; CQ: chloroquine; CTNNB1: catenin beta 1; DDIT3: DNA damage inducible transcript 3; EC: endometrial cancer; EGFR: epidermal growth factor receptor; EH: endometrial hyperplasia; EIF4E: eukaryotic translation initiation factor 4E; EPHB2/ERK: EPH receptor B2; ER: endoplasmic reticulum; ERBB2: er-b2 receptor tyrosine kinase 2; ERVW-1: endogenous retrovirus group W member 1, envelope; ESR1: estrogen receptor 1; FSH: follicle-stimulating hormone; GCG/GLP1: glucagon; GFP: green fluorescent protein; GIP: gastric inhibitory polypeptide; GLP1R: glucagon-like peptide-1 receptor; GLS: glutaminase; H2AX: H2A.X variant histone; HIF1A: hypoxia inducible factor 1 alpha; HMGB1: high mobility group box 1; HOTAIR: HOX transcript antisense RNA; HSPA5: heat shock protein family A (HSP70) member 5; HSPA8: heat shock protein family A (HSP70) member 8; IGF1: insulin like growth factor 1; IL27: interleukin 27; INS: insulin; ISL: isoliquiritigenin; KRAS: KRAS proto-oncogene, GTPase; LAMP2: lysosomal-associated membrane protein 2; lncRNA: long-non-coding RNA; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPK8: mitogen-activated protein kinase 8; MAPK9: mitogen-activated protein kinase 9; MPA: medroxyprogesterone acetate; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; MYCBP: MYC-binding protein; NFE2L2: nuclear factor, erythroid 2 like 2; NFKB: nuclear factor kappa B; NFKBIA: NFKB inhibitor alpha; NK: natural killer; NR5A1: nuclear receptor subfamily 5 group A member 1; PARP1: poly(ADP-ribose) polymerase 1; PAX2: paired box 2; PDK1: pyruvate dehydrogenase kinase 1; PDX: patient-derived xenograft; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PIK3R1: phosphoinositide-3-kinase regulatory subunit 1; PIKFYVE: phosphoinositide kinase, FYVE-type zinc finger containing; PPD: protopanaxadiol; PRKCD: protein kinase C delta; PROM1/CD133: prominin 1; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PTEN: phosphatase and tensin homolog; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RFP: red fluorescent protein; RPS6KB1/S6K1: ribosomal protein S6 kinase B1; RSV: resveratrol; SGK1: serum/glucocorticoid regulated kinase 1; SGK3: serum/glucocorticoid regulated kinase family member 3; SIRT: sirtuin; SLS: stone-like structures; SMAD2: SMAD family member 2; SMAD3: SMAD family member 3; SQSTM1: sequestosome 1; TALEN: transcription activator-like effector nuclease; TGFBR2: transforming growth factor beta receptor 2; TP53: tumor protein p53; TRIB3: tribbles pseudokinase 3; ULK1: unc-51 like autophagy activating kinase 1; ULK4: unc-51 like kinase 4; VEGFA: vascular endothelial growth factor A; WIPI2: WD repeat domain, phosphoinositide interacting 2; XBP1: X-box binding protein 1; ZFYVE1: zinc finger FYVE domain containing 1.

摘要

自噬是一种高度保守的分解代谢过程，也是长寿蛋白质和细胞质细胞器降解的主要细胞途径。越来越多的证据表明，自噬是一种不可或缺的生物功能，有助于维持正常的组织稳态和代谢适应性，当其改变时，也可能对正常细胞功能造成严重后果。最近积累的数据表明，自噬在人类子宫内膜的多种生理和病理生理条件中发挥着关键作用，子宫内膜是人体最熟练的自我再生组织之一，也是胎盘物种生殖功能的重要参与者。当前的综述重点介绍了有关正常和癌性子宫内膜组织自噬过程的最新发现。讨论了当前旨在治疗性利用自噬的研究工作以及所使用的方法。

缩写： 3-MA：3-甲基腺嘌呤；ACACA（乙酰辅酶A羧化酶α）；AICAR：5-氨基咪唑-4-甲酰亚胺核苷；AKT：AKT 丝氨酸/苏氨酸激酶；AMPK：AMP 激活的蛋白激酶；ATG：自噬相关；ATG12：自噬相关12；ATG16L1：自噬相关16样1；ATG3：自噬相关3；ATG4C：自噬相关的4C半胱氨酸肽酶；ATG5：自噬相关5；ATG7：自噬相关7；ATG9：自噬相关9；Baf A1：巴弗洛霉素 A ₁; BAX：BCL2相关X，凋亡调节因子；BCL2：BCL2凋亡调节因子；BECN1: 贝克林 1; CACNA1D：钙电压门控通道亚基 alpha1 D；CASP3: 半胱天冬酶 3; CASP7: 半胱天冬酶 7; CASP8: 半胱天冬酶 8; CASP9: 半胱天冬酶 9; CD44：CD44分子（印度血型）；CDH1：钙粘蛋白1；CDKN1A：细胞周期蛋白依赖性激酶抑制剂1A；CDKN2A：细胞周期蛋白依赖性激酶抑制剂2A；CMA：分子伴侣介导的自噬；CQ：氯喹；CTNNB1：连环蛋白β1；DDIT3：DNA损伤诱导转录物3；EC：子宫内膜癌；EGFR：表皮生长因子受体；EH：子宫内膜增生；EIF4E：真核翻译起始因子4E；EPHB2/ERK：EPH 受体 B2；ER：内质网；ERBB2：er-b2受体酪氨酸激酶2；ERVW-1：内源性逆转录病毒W组成员1，包膜；ESR1：雌激素受体1；FSH：卵泡刺激素；GCG/GLP1：胰高血糖素；GFP：绿色荧光蛋白；GIP：抑胃多肽；GLP1R：胰高血糖素样肽-1受体；GLS：谷氨酰胺酶；H2AX：H2A.X 变体组蛋白；HIF1A：缺氧诱导因子1α；HMGB1：高机动组盒1；HOTAIR：HOX转录反义RNA；HSPA5：热休克蛋白家族 A (HSP70) 成员 5；HSPA8：热休克蛋白家族 A (HSP70) 成员 8；IGF1：胰岛素样生长因子1；IL27：白细胞介素27；INS：胰岛素；ISL: 异甘草素；KRAS：KRAS原癌基因，GTPase；LAMP2：溶酶体相关膜蛋白2；lncRNA：长链非编码RNA；MAP1LC3A/LC3A：微管相关蛋白1轻链3α；MAP1LC3B/LC3B：微管相关蛋白1轻链3β；MAPK8：丝裂原激活蛋白激酶8；MAPK9: 丝裂原激活蛋白激酶 9; MPA：醋酸甲羟孕酮；MTOR：雷帕霉素激酶的机制靶点；MTORC1：雷帕霉素激酶复合物 1 的机制靶点；MTORC2：雷帕霉素激酶复合物 2 的机制靶点；MYCBP：MYC 结合蛋白；NFE2L2：核因子，红细胞2样2；NFKB：核因子κB；NFKBIA：NFKB抑制剂α；NK：自然杀手；NR5A1：核受体亚家族5 A组成员1；PARP1：聚（ADP-核糖）聚合酶1；PAX2：配对盒2；PDK1：丙酮酸脱氢酶激酶1；PDX：患者来源的异种移植物；PIK3C3/Vps34：磷脂酰肌醇3-激酶催化亚基3型；PIK3CA：磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α；PIK3R1：磷酸肌醇-3-激酶调节亚基1；PIKFYVE：磷酸肌醇激酶，含有FYVE型锌指；PPD：原人参二醇；PRKCD：蛋白激酶C δ；PROM1/CD133: 突出蛋白 1; PtdIns3K：III类磷脂酰肌醇3-激酶；PtdIns3P：3-磷酸磷脂酰肌醇；PTEN：磷酸酶和张力蛋白同系物；RB1CC1/FIP200：RB1感应线圈1；RFP：红色荧光蛋白；RPS6KB1/S6K1：核糖体蛋白S6激酶B1；RSV: 白藜芦醇；SGK1：血清/糖皮质激素调节激酶1；SGK3：血清/糖皮质激素调节激酶家族成员3；SIRT：去乙酰化酶；SLS：类似石头的结构；SMAD2：SMAD家庭成员2名；SMAD3：SMAD家族成员3；SQSTM1: 隔离体 1; TALEN：转录激活子样效应核酸酶；TGFBR2：转化生长因子β受体2；TP53：肿瘤蛋白p53；TRIB3: tribbles 假激酶 3; ULK1：unc-51 样自噬激活激酶 1；ULK4：unc-51 样激酶 4；VEGFA：血管内皮生长因子A；WIPI2：WD重复结构域，磷酸肌醇相互作用2；XBP1：X盒结合蛋白1；ZFYVE1：含有1的锌指FYVE结构域。