Role of epithelial-mesenchymal transition factor SNAI1 and its targets in ovarian cancer aggressiveness

Abstract

Ovarian cancer remains the most lethal gynecologic malignancy in the USA. For over twenty years, epithelial-mesenchymal transition (EMT) has been characterized extensively in development and disease. The dysregulation of this process in cancer has been identified as a mechanism by which epithelial tumors become more aggressive, allowing them to survive and invade distant tissues. This occurs in part due to the increased expression of the EMT transcription factor, SNAI1 (Snail). In the case of epithelial ovarian cancer, Snail has been shown to contribute to cancer invasion, stemness, chemoresistance, and metabolic changes. Thus, in this review, we focus on summarizing current findings on the role of EMT (specifically, factors downstream of Snail) in determining ovarian cancer aggressiveness.

Keywords

Snail / ovarian cancer / epithelial-mesenchymal transition / chemoresistance / cancer stemness / cancer invasion / metastasis / cancer aggressiveness

References

[1] Siegel RL,Fuchs HE.Cancer statistics, 2021.CA Cancer J Clin2021;71:7-33

[2] Barnes BM,Tighe A.Distinct transcriptional programs stratify ovarian cancer cell lines into the five major histological subtypes.Genome Med2021;13:140 PMCID:PMC8408985

[3] Morden CR,Sliwowski M.Chromosome instability is prevalent and dynamic in high-grade serous ovarian cancer patient samples.Gynecol Oncol2021;161:769-78

[4] Reid BM,Chen YA.Genome-wide analysis of common copy number variation and epithelial ovarian cancer risk.Cancer Epidemiol Biomarkers Prev2019;28:1117-26 PMCID:PMC6606353

[5] Hu Z,Alsaadi A.The repertoire of serous ovarian cancer non-genetic heterogeneity revealed by single-cell sequencing of normal fallopian tube epithelial cells.Cancer Cell2020;37:226-42.e7

[6] Torre LA,DeSantis CE.Ovarian cancer statistics, 2018.CA Cancer J Clin2018;68:284-96 PMCID:PMC6621554

[7] Lu M,Xu B.Using machine learning to predict ovarian cancer.Int J Med Inform2020;141:104195

[8] Kurnit KC,Lengyel E.Updates and new options in advanced epithelial ovarian cancer treatment.Obstet Gynecol2021;137:108-21 PMCID:PMC7737875

[9] Yang J,Berx G.EMT International Association (TEMTIA)Guidelines and definitions for research on epithelial-mesenchymal transition.Nat Rev Mol Cell Biol2020;21:341-52 PMCID:PMC7250738

[10] Rho SB,Kim BR.Snail promotes cancer cell proliferation via its interaction with the BIRC3.Biomol Ther2022;30:380-8 PMCID:PMC9252879

[11] Baulida J.Snail1-driven plasticity of epithelial and mesenchymal cells sustains cancer malignancy.Biochim Biophys Acta2015;1856:55-61

[12] Wang H,Hojo N.The epithelial-mesenchymal transcription factor SNAI1 represses transcription of the tumor suppressor miRNA let-7 in cancer.Cancers2021;13:1469 PMCID:PMC8004805

[13] Kurrey NK,Joglekar AV.Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells.Stem Cells2009;27:2059-68

[14] Brabletz T,Nieto MA.EMT in cancer.Nat Rev Cancer2018;18:128-34

[15] Rowe RG,Hu Y.Mesenchymal cells reactivate snail1 expression to drive three-dimensional invasion programs.J Cell Biol2009;184:399-408 PMCID:PMC2646556

[16] Galindo-Pumariño C,Castillo ME.SNAI1-expressing fibroblasts and derived-extracellular matrix as mediators of drug resistance in colorectal cancer patients.Toxicol Appl Pharmacol2022;450:116171

[17] Sala L,Stanisavljevic J.Abrogation of myofibroblast activities in metastasis and fibrosis by methyltransferase inhibition.Int J Cancer2019;145:3064-77

[18] Zeisberg M.Biomarkers for epithelial-mesenchymal transitions.J Clin Invest2009;119:1429-37 PMCID:PMC2689132

[19] Thiery JP,Huang RY.Epithelial-mesenchymal transitions in development and disease.Cell2009;139:871-90

[20] Sharma A,Currenti J.Oncofetal reprogramming in tumour development and progression.Nat Rev Cancer2022;22:593-602

[21] Grau Y,Simpson P.Mutations and chromosomal rearrangements affecting the expression of snail, a gene involved in embryonic patterning in DROSOPHILA MELANOGASTER.Genetics1984;108:347-60 PMCID:PMC1202410

[22] Ciruna B.FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak.Dev Cell2001;1:37-49

[23] Dale JK,Chal J.Oscillations of the snail genes in the presomitic mesoderm coordinate segmental patterning and morphogenesis in vertebrate somitogenesis.Dev Cell2006;10:355-66

[24] Tyser RCV,Nakanoh S,Scialdone A.Single-cell transcriptomic characterization of a gastrulating human embryo.Nature2021;600:285-9

[25] Dubrulle J,Pourquié O.FGF signaling controls somite boundary position and regulates segmentation clock control of spatiotemporal Hox gene activation.Cell2001;106:219-32

[26] Aulehla A,Brand-Saberi B.Wnt3a plays a major role in the segmentation clock controlling somitogenesis.Dev Cell2003;4:395-406

[27] Chu LF,Ni Z.An in vitro human segmentation clock model derived from embryonic stem cells.Cell Rep2019;28:2247-55.e5 PMCID:PMC6814198

[28] Dias A,Wymeersch FJ.A Tgfbr1/Snai1-dependent developmental module at the core of vertebrate axial elongation.Elife2020;9:e56615 PMCID:PMC7324159

[29] Nicholson HA,Clarke RG,Ferguson MJ.Fibroblast growth factor signalling influences homologous recombination-mediated DNA damage repair to promote drug resistance in ovarian cancer.Br J Cancer2022;127:1340-51 PMCID:PMC9519926

[30] Sun Y,Zhang Q,Xu G.Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling.Tumour Biol2017;39:1010428317712592

[31] Cano A,Rodrigo I.The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression.Nat Cell Biol2000;2:76-83

[32] Batlle E,Francí C.The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells.Nat Cell Biol2000;2:84-9

[33] Stemmler MP,Brabletz S.Non-redundant functions of EMT transcription factors.Nat Cell Biol2019;21:102-12

[34] Stone RC,Ojeh N.Epithelial-mesenchymal transition in tissue repair and fibrosis.Cell Tissue Res2016;365:495-506 PMCID:PMC5011038

[35] Gharbia FZ,Moqidem YA.Adult skin fibroblast state change in murine wound healing.Sci Rep2023;13:886 PMCID:PMC9845335

[36] Yan C,Garner WL.Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-alpha through bone morphogenic protein-2.Am J Pathol2010;176:2247-58 PMCID:PMC2861090

[37] Qi R,Jiang Y.Snai1-induced partial epithelial-mesenchymal transition orchestrates p53-p21-mediated G2/M arrest in the progression of renal fibrosis via NF-κB-mediated inflammation.Cell Death Dis2021;12:44 PMCID:PMC7790819

[38] Dongre A.New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer.Nat Rev Mol Cell Biol2019;20:69-84

[39] Miyoshi A,Kido S.Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma.Br J Cancer2005;92:252-8 PMCID:PMC2361838

[40] Mani SA,Liao MJ.The epithelial-mesenchymal transition generates cells with properties of stem cells.Cell2008;133:704-15 PMCID:PMC2728032

[41] Jolly MK,Bhatia S.Measuring and modelling the epithelial- mesenchymal hybrid state in cancer: clinical implications.Cells Tissues Organs2022;211:110-33

[42] Hay ED.An overview of epithelio-mesenchymal transformation.Acta Anat1995;154:8-20

[43] Pastushenko I.EMT transition states during tumor progression and metastasis.Trends Cell Biol2019;29:212-26

[44] Tan TZ,Huang RY.Functional genomics identifies five distinct molecular subtypes with clinical relevance and pathways for growth control in epithelial ovarian cancer.EMBO Mol Med2013;5:1051-66 PMCID:PMC3721473

[45] Pang QY,Sundararajan V.3D genome organization in the epithelial-mesenchymal transition spectrum.Genome Biol2022;23:121 PMCID:PMC9150291

[46] Strauss R,Liu Y.Analysis of epithelial and mesenchymal markers in ovarian cancer reveals phenotypic heterogeneity and plasticity.PLoS One2011;6:e16186 PMCID:PMC3021543

[47] Huang RY,Tan TZ.An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530).Cell Death Dis2013;4:e915 PMCID:PMC3847320

[48] Klymenko Y,Stack MS.Complex determinants of epithelial: mesenchymal phenotypic plasticity in ovarian cancer.Cancers2017;9:104 PMCID:PMC5575607

[49] Gonzalez VD,Chen TJ.Commonly occurring cell subsets in high-grade serous ovarian tumors identified by single-cell mass cytometry.Cell Rep2018;22:1875-88 PMCID:PMC8556706

[50] Takano S,Bakir B.Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization.Genes Dev2016;30:233-47 PMCID:PMC4719312

[51] Watanabe K,Sun P.Mammary morphogenesis and regeneration require the inhibition of EMT at terminal end buds by Ovol2 transcriptional repressor.Dev Cell2014;29:59-74 PMCID:PMC4062651

[52] Hong T,Ta CH,Nie Q.An Ovol2-Zeb1 mutual inhibitory circuit governs bidirectional and multi-step transition between epithelial and mesenchymal states.PLoS Comput Biol2015;11:e1004569 PMCID:PMC4640575

[53] Jolly MK,Jia D.Stability of the hybrid epithelial/mesenchymal phenotype.Oncotarget2016;7:27067-84 PMCID:PMC5053633

[54] Bocci F,Tripathi SC.Numb prevents a complete epithelial-mesenchymal transition by modulating Notch signalling.J R Soc Interface2017;14:20170512 PMCID:PMC5721160

[55] Varankar SS,Abraham A.Functional balance between Tcf21-Slug defines cellular plasticity and migratory modalities in high grade serous ovarian cancer cell lines.Carcinogenesis2020;41:515-26

[56] Ocaña OH,Fabra A.Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1.Cancer Cell2012;22:709-24

[57] Strauss R,Liu Y.Epithelial phenotype confers resistance of ovarian cancer cells to oncolytic adenoviruses.Cancer Res2009;69:5115-25 PMCID:PMC2738419

[58] Muñoz-Galván S.Leveraging genomics, transcriptomics, and epigenomics to understand the biology and chemoresistance of ovarian cancer.Cancers2021;13:4029 PMCID:PMC8391219

[59] Yu KH,Wang F.Deciphering serous ovarian carcinoma histopathology and platinum response by convolutional neural networks.BMC Med2020;18:236 PMCID:PMC7433108

[60] Wang J,Hornicek FJ,Duan Z.RNA sequencing (RNA-Seq) and its application in ovarian cancer.Gynecol Oncol2019;152:194-201

[61] Tothill RW,George J.Australian Ovarian Cancer Study GroupNovel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome.Clin Cancer Res2008;14:5198-208

[62] Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma.Nature2011;474:609-15 PMCID:PMC3163504

[63] Hollis RL,Michie CO.Multiomic characterization of high-grade serous ovarian carcinoma enables high-resolution patient stratification.Clin Cancer Res2022;28:3546-56 PMCID:PMC9662902

[64] Cook DP.Context specificity of the EMT transcriptional response.Nat Commun2020;11:2142 PMCID:PMC7195456

[65] Kan T,Ip PP.Single-cell EMT-related transcriptional analysis revealed intra-cluster heterogeneity of tumor cell clusters in epithelial ovarian cancer ascites.Oncogene2020;39:4227-40

[66] Xu J,Chen K.Single-cell RNA sequencing reveals the tissue architecture in human high-grade serous ovarian cancer.Clin Cancer Res2022;28:3590-602 PMCID:PMC9662915

[67] McCorry AM,Longley DB,Dunne PD.Epithelial-to-mesenchymal transition signature assessment in colorectal cancer quantifies tumour stromal content rather than true transition.J Pathol2018;246:422-6 PMCID:PMC6282832

[68] Stanisavljevic J,Herrera M.Snail1-expressing fibroblasts in the tumor microenvironment display mechanical properties that support metastasis.Cancer Res2015;75:284-95

[69] Stur E,Xu M.Spatially resolved transcriptomics of high-grade serous ovarian carcinoma.iScience2022;25:103923 PMCID:PMC8891954

[70] Zhu Y,Sheng J.SIO: a spatioimageomics pipeline to identify prognostic biomarkers associated with the ovarian tumor microenvironment.Cancers2021;13:1777 PMCID:PMC8068305

[71] Imai T,Wang C.Hypoxia attenuates the expression of E-cadherin via up-regulation of snail in ovarian carcinoma cells.Am J Pathol2003;163:1437-47 PMCID:PMC1868286

[72] Craene B, van Roy F, Berx G. Unraveling signalling cascades for the snail family of transcription factors.Cell Signal2005;17:535-47

[73] Ichikawa MK,Itoh Y.Ets family proteins regulate the EMT transcription factors snail and ZEB in cancer cells.FEBS Open Bio2022;12:1353-64 PMCID:PMC9249322

[74] Hapke RY.Hypoxia-induced epithelial to mesenchymal transition in cancer.Cancer Lett2020;487:10-20 PMCID:PMC7336507

[75] Thibault B,Delord JP.Ovarian cancer microenvironment: implications for cancer dissemination and chemoresistance acquisition.Cancer Metastasis Rev2014;33:17-39

[76] Mogi K,Iyoshi S.Ovarian cancer-associated mesothelial cells: transdifferentiation to minions of cancer and orchestrate developing peritoneal dissemination.Cancers2021;13:1352 PMCID:PMC8002484

[77] Worzfeld T,Huber M.The unique molecular and cellular microenvironment of ovarian cancer.Front Oncol2017;7:24 PMCID:PMC5319992

[78] Cho A,Colvin EK.The extracellular matrix in epithelial ovarian cancer - a piece of a puzzle.Front Oncol2015;5:245 PMCID:PMC4629462

[79] Gao Q,Xu S.Heterotypic CAF-tumor spheroids promote early peritoneal metastatis of ovarian cancer.J Exp Med2019;216:688-703 PMCID:PMC6400537

[80] Madden EC,Logue SE.Tumour cell secretome in chemoresistance and tumour recurrence.Trends Cancer2020;6:489-505

[81] Wang S,Liu D.Matrix metalloproteinase expressions play important role in prediction of ovarian cancer outcome.Sci Rep2019;9:11677 PMCID:PMC6691000

[82] Shay G,Fingleton B.Moving targets: emerging roles for MMPs in cancer progression and metastasis.Matrix Biol2015;44-6:200-6 PMCID:PMC4564058

[83] Pang L,Li S.Membrane type 1-matrix metalloproteinase induces epithelial-to-mesenchymal transition in esophageal squamous cell carcinoma: Observations from clinical and in vitro analyses.Sci Rep2016;6:22179 PMCID:PMC4768157

[84] Li Y,Wang F.Role of MMP-9 in epithelial-mesenchymal transition of thyroid cancer.World J Surg Oncol2020;18:181 PMCID:PMC7376963

[85] Liu Y,Feng J.MT2-MMP induces proteolysis and leads to EMT in carcinomas.Oncotarget2016;7:48193-205 PMCID:PMC5217011

[86] Kurrey NK,Bapat SA.Snail and Slug are major determinants of ovarian cancer invasiveness at the transcription level.Gynecol Oncol2005;97:155-65

[87] Jin H,Zhang T.Snail is critical for tumor growth and metastasis of ovarian carcinoma.Int J Cancer2010;126:2102-11

[88] Ohkubo T.The transcription factor snail downregulates the tight junction components independently of E-cadherin downregulation.J Cell Sci2004;117:1675-85

[89] Whiteman EL,Fearon ER.The transcription factor snail represses Crumbs3 expression and disrupts apico-basal polarity complexes.Oncogene2008;27:3875-9 PMCID:PMC2533733

[90] Massoumi R,Hellerbrand C.Down-regulation of CYLD expression by snail promotes tumor progression in malignant melanoma.J Exp Med2009;206:221-32 PMCID:PMC2626666

[91] Kashyap A,Ergül N.The human Lgl polarity gene, Hugl-2, induces MET and suppresses Snail tumorigenesis.Oncogene2013;32:1396-407

[92] Unternaehrer JJ,Kim K.The epithelial-mesenchymal transition factor snail paradoxically enhances reprogramming.Stem Cell Reports2014;3:691-8 PMCID:PMC4235745

[93] Brayman M,Carson DD.MUC1: a multifunctional cell surface component of reproductive tissue epithelia.Reprod Biol Endocrinol2004;2:4 PMCID:PMC320498

[94] Guaita S,Franci C.Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression.J Biol Chem2002;277:39209-16

[95] Siemens H,Hünten S.MiR-34 and snail form a double-negative feedback loop to regulate epithelial-mesenchymal transitions.Cell Cycle2011;10:4256-71

[96] Díaz-López A,Moreno-Bueno G.Zeb1 and snail1 engage miR-200f transcriptional and epigenetic regulation during EMT.Int J Cancer2015;136:E62-73

[97] Park SM,Lengyel E.The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2.Genes Dev2008;22:894-907 PMCID:PMC2279201

[98] Burk U,Wellner U.A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells.EMBO Rep2008;9:582-9 PMCID:PMC2396950

[99] Beach S,Park S.Snail is a repressor of RKIP transcription in metastatic prostate cancer cells.Oncogene2008;27:2243-8 PMCID:PMC2933472

[100] Kim NH,Lee J.Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress.Nat Commun2017;8:14374 PMCID:PMC5309788

[101] Ganesan R,Gomez-Cambronero J.The transcription factors Slug (SNAI2) and snail (SNAI1) regulate phospholipase D (PLD) promoter in opposite ways towards cancer cell invasion.Mol Oncol2016;10:663-76 PMCID:PMC4870114

[102] Escriva M,Herranz N.Repression of PTEN phosphatase by snail1 transcriptional factor during gamma radiation-induced apoptosis.Mol Cell Biol2008;28:1528-40 PMCID:PMC2258777

[103] Sundararajan V,Tan TZ,Thiery JP.SNAI1 recruits HDAC1 to suppress SNAI2 transcription during epithelial to mesenchymal transition.Sci Rep2019;9:8295 PMCID:PMC6549180

[104] Pálmer HG,García JM.The transcription factor Snail represses vitamin D receptor expression and responsiveness in human colon cancer.Nat Med2004;10:917-9

[105] Ly TM,Lee MC.Snail upregulates transcription of FN, LEF, COX2, and COL1A1 in hepatocellular carcinoma: a general model established for snail to transactivate mesenchymal genes.Cells2021;10:2202 PMCID:PMC8467536

[106] Taki M,Baba T.Snail promotes ovarian cancer progression by recruiting myeloid-derived suppressor cells via CXCR2 ligand upregulation.Nat Commun2018;9:1685 PMCID:PMC5923228

[107] Jordà M,Vinyals A.Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor.J Cell Sci2005;118:3371-85

[108] Baulida J,Herreros AG.Snail1: a transcriptional factor controlled at multiple levels.J Clin Med2019;8:757 PMCID:PMC6616578

[109] Chen L,Sun L.Snail driving alternative splicing of CD44 by ESRP1 enhances invasion and migration in epithelial ovarian cancer.Cell Physiol Biochem2017;43:2489-504

[110] Cui H,Guo D.DNA methyltransferase 3A isoform b contributes to repressing E-cadherin through cooperation of DNA methylation and H3K27/H3K9 methylation in EMT-related metastasis of gastric cancer.Oncogene2018;37:4358-71 PMCID:PMC6085280

[111] Dong P,Watari H.MiR-137 and miR-34a directly target snail and inhibit EMT, invasion and sphere-forming ability of ovarian cancer cells.J Exp Clin Cancer Res2016;35:132 PMCID:PMC5011787

[112] Pearson GW.Control of invasion by epithelial-to-mesenchymal transition programs during metastasis.J Clin Med2019;8:646 PMCID:PMC6572027

[113] Aiello NM,Norgard RJ.EMT subtype influences epithelial plasticity and mode of cell migration.Dev Cell2018;45:681-95.e4 PMCID:PMC6014628

[114] Loret N,Tummers P.The role of epithelial-to-mesenchymal plasticity in ovarian cancer progression and therapy resistance.Cancers2019;11:838 PMCID:PMC6628067

[115] Jolly MK,Sheth M.Hybrid epithelial/mesenchymal phenotypes promote metastasis and therapy resistance across carcinomas.Pharmacol Ther2019;194:161-84

[116] Pal A,Paolini R,Puram SV.Partial EMT in head and neck cancer biology: a spectrum instead of a switch.Oncogene2021;40:5049-65 PMCID:PMC8934590

[117] Liao TT.Hybrid epithelial/mesenchymal state in cancer metastasis: clinical significance and regulatory mechanisms.Cells2020;9:623 PMCID:PMC7140395

[118] George JT,Xu S,Levine H.Survival outcomes in cancer patients predicted by a partial EMT gene expression scoring metric.Cancer Res2017;77:6415-28 PMCID:PMC5690883

[119] Li CF,Ho YH.Snail-induced claudin-11 prompts collective migration for tumour progression.Nat Cell Biol2019;21:251-62

[120] Pradeep S,Wu SY.Hematogenous metastasis of ovarian cancer: rethinking mode of spread.Cancer Cell2014;26:77-91 PMCID:PMC4100212

[121] Lee M,Cho Y.Predictive value of circulating tumor cells (CTCs) captured by microfluidic device in patients with epithelial ovarian cancer.Gynecol Oncol2017;145:361-5

[122] Aponte PM.Stemness in cancer: stem cells, cancer stem cells, and their microenvironment.Stem Cells Int2017;2017:5619472 PMCID:PMC5394399

[123] Reya T,Clarke MF.Stem cells, cancer, and cancer stem cells.Nature2001;414:105-11

[124] Bapat SA,Koppikar CB.Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer.Cancer Res2005;65:3025-9

[125] Suster N, Virant-Klun I. Presence and role of stem cells in ovarian cancer.World J Stem Cells2019;11:383-97 PMCID:PMC6682502

[126] Hahn S,Siemens H,Hermeking H.Snail and miR-34a feed-forward regulation of ZNF281/ZBP99 promotes epithelial-mesenchymal transition.EMBO J2013;32:3079-95 PMCID:PMC3844956

[127] Bracken CP,Kolesnikoff N.A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition.Cancer Res2008;68:7846-54

[128] Wellner U,Burk UC.The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs.Nat Cell Biol2009;11:1487-95

[129] Brabletz S.The ZEB/miR-200 feedback loop - a motor of cellular plasticity in development and cancer?.EMBO Rep2010;11:670-7 PMCID:PMC2933868

[130] Li Q,Chiu PCN.Mir-let-7a/g enhances uterine receptivity via suppressing Wnt/β-Catenin under the modulation of ovarian hormones.Reprod Sci2020;27:1164-74

[131] Yang WH,Huang CH.RAC1 activation mediates Twist1-induced cancer cell migration.Nat Cell Biol2012;14:366-74

[132] Worringer KA,Hayashi Y.The let-7/LIN-41 pathway regulates reprogramming to human induced pluripotent stem cells by controlling expression of prodifferentiation genes.Cell Stem Cell2014;14:40-52 PMCID:PMC3982312

[133] Morel AP,Thomas C,Ansieau S.Generation of breast cancer stem cells through epithelial-mesenchymal transition.PLoS One2008;3:e2888 PMCID:PMC2492808

[134] Chiou SH,Chou YT.Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation.Cancer Res2010;70:10433-44

[135] Yin X,Zheng SS.Coexpression of gene Oct4 and Nanog initiates stem cell characteristics in hepatocellular carcinoma and promotes epithelial-mesenchymal transition through activation of Stat3/snail signaling.J Hematol Oncol2015;8:23 PMCID:PMC4377043

[136] Jolly MK,Boareto M.Coupling the modules of EMT and stemness: a tunable ‘stemness window’ model.Oncotarget2015;6:25161-74 PMCID:PMC4694822

[137] Jolly MK,Lu M,Levine H.Towards elucidating the connection between epithelial-mesenchymal transitions and stemness.J R Soc Interface2014;11:20140962 PMCID:PMC4223923

[138] Wang Y,Chai K,Zhou BP.The role of snail in EMT and tumorigenesis.Curr Cancer Drug Targets2013;13:963-72 PMCID:PMC4004763

[139] Saxena K,Balamurugan K.Hypoxia, partial EMT and collective migration: emerging culprits in metastasis.Transl Oncol2020;13:100845 PMCID:PMC7419667

[140] Kröger C,Mraz J.Acquisition of a hybrid E/M state is essential for tumorigenicity of basal breast cancer cells.Proc Natl Acad Sci USA2019;116:7353-62 PMCID:PMC6462070

[141] Hojo N,Wang H.Snail knockdown reverses stemness and inhibits tumour growth in ovarian cancer.Sci Rep2018;8:8704 PMCID:PMC5992154

[142] Ahmed N,Leung D,Kannourakis G.Tumour microenvironment and metabolic plasticity in cancer and cancer stem cells: perspectives on metabolic and immune regulatory signatures in chemoresistant ovarian cancer stem cells.Semin Cancer Biol2018;53:265-81

[143] Dong C,Wu Y.Loss of FBP1 by snail-mediated repression provides metabolic advantages in basal-like breast cancer.Cancer Cell2013;23:316-31 PMCID:PMC3703516

[144] Grassi ML,Thomé CH,Poersch A.Proteomic analysis of ovarian cancer cells during epithelial-mesenchymal transition (EMT) induced by epidermal growth factor (EGF) reveals mechanisms of cell cycle control.J Proteomics2017;151:2-11

[145] Leung D,Lokman NA.Platinum-resistance in epithelial ovarian cancer: an interplay of epithelial-mesenchymal transition interlinked with reprogrammed metabolism.J Transl Med2022;20:556 PMCID:PMC9719259

[146] Kobayashi H.Recent advances in understanding the metabolic plasticity of ovarian cancer: a systematic review.Heliyon2022;8:e11487 PMCID:PMC9668530

[147] Daly MB,Berry MP.Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 2.2021, NCCN clinical practice guidelines in oncology.J Natl Compr Canc Netw2021;19:77-102

[148] Armstrong DK,Bakkum-Gamez JN.Ovarian cancer, version 2.2020, NCCN clinical practice guidelines in oncology.J Natl Compr Canc Netw2021;19:191-226

[149] Kim H,George E.Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models.Nat Commun2020;11:3726 PMCID:PMC7381609

[150] Wang H,Wei W.Regulation of ATP-binding cassette subfamily B member 1 by snail contributes to chemoresistance in colorectal cancer.Cancer Sci2020;111:84-97 PMCID:PMC6942434

[151] Saxena M,Pathak H.Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters.Cell Death Dis2011;2:e179 PMCID:PMC3199722

[152] Haslehurst AM,Dharsee M.EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer.BMC Cancer2012;12:91 PMCID:PMC3342883

[153] Seo J,Kang E.The role of epithelial-mesenchymal transition-regulating transcription factors in anti-cancer drug resistance.Arch Pharm Res2021;44:281-92 PMCID:PMC8009775

[154] Sundararajan V,Zea Tan T.SNAI1-driven sequential EMT changes attributed by selective chromatin enrichment of RAD21 and GRHL2.Cancers2020;12:1140 PMCID:PMC7281482

[155] Harney AS,LaBonne C.Targeted inactivation of snail family EMT regulatory factors by a Co(III)-Ebox conjugate.PLoS One2012;7:e32318 PMCID:PMC3290632

[156] Lee SH,Jung YS.Antitumor effect of novel small chemical inhibitors of snail-p53 binding in K-Ras-mutated cancer cells.Oncogene2010;29:4576-87

[157] Ferrari-Amorotti G,Esteki R.Inhibiting interactions of lysine demethylase LSD1 with snail/slug blocks cancer cell invasion.Cancer Res2013;73:235-45 PMCID:PMC3537890

[158] Ferrari-Amorotti G,Shen F.Suppression of invasion and metastasis of triple-negative breast cancer lines by pharmacological or genetic inhibition of slug activity.Neoplasia2014;16:1047-58 PMCID:PMC4557365

[159] Li HM,Li Y.A potent CBP/p300-snail interaction inhibitor suppresses tumor growth and metastasis in wild-type p53-expressing cancer.Sci Adv2020;6:eaaw8500 PMCID:PMC7176418

[160] Ren BX,Li HM,Wu ZQ.The antibiotic drug trimethoprim suppresses tumour growth and metastasis via targeting snail.Br J Pharmacol2022;179:2659-77

[161] Cui H,Lei Y.Design and synthesis of dual inhibitors targeting snail and histone deacetylase for the treatment of solid tumour cancer.Eur J Med Chem2022;229:114082