Abstract
Currently, clinical biomarkers are urgently needed to improve patient management to guide personal therapy for cancer. In this study, we investigate the deregulation of Zeb-1 in prostate cancer (PC) Tunisian patients. Expression patterns of the Zeb-1 were investigated in prostate adenocarcinoma and benign prostate biopsies using quantitative real-time reverse transcription-polymerase chain reaction (RT-qPCR) and 2-ΔΔCt method. Statistical analysis was used to identify differences across groups depending on gene expression level. Furthermore, we exploited a follow-up over 15 years to correlate Zeb-1 deregulation and clinical outcomes in PC patients. Based on ROC curve analyses, the AUC was found in discriminating PC patients from controls (AUC = 0.757; p < 0.001). In addition, the higher expression level was significantly associated with PSA, Digital Rectal Examination, Gleason score, tumor stage, and distant lymph node metastases. Moreover, Zeb-1 overexpression was correlated with shorter overall survival (OS) (p = 0.042), poor progression-free survival (PFS) (p = 0.007), and with resistance to taxanes (p = 0.012). Our data provide the aberrant expression of Zeb-1 in PC patients suggesting its potential diagnostic, prognostic, and theranostic role. Further functional studies are mandatory to strengthen these results and to uncover the molecular mechanism of this neoplasm.
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Data sharing does not apply to this article as no datasets were generated or analyzed during the current study.
References
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin 68(6):394–424. https://doi.org/10.3322/caac.21492
Cha YJ, Lee JH, Han HH, Kim BG, Kang S, Choi YD, Cho NH (2016) MicroRNA alteration and putative target genes in high-grade prostatic intraepithelial neoplasia and prostate cancer: STAT3 and ZEB1 are upregulated during prostate carcinogenesis. Prostate 76(10):937–947. https://doi.org/10.1002/pros.23183
Di Gregorio J, Robuffo I, Spalletta S, Giambuzzi G, De Iuliis V, Toniato E, Flati V (2020) The epithelial-to-mesenchymal transition as a possible therapeutic target in fibrotic disorders. Front Cell Dev Biol 8:607483. https://doi.org/10.3389/fcell.2020.607483
Duffy MJ (2020) Biomarkers for prostate cancer: prostate-specific antigen and beyond. Clin Chem Lab Med (CCLM) 58(3):326–339. https://doi.org/10.1515/cclm-2019-0693
Farfán N, Ocarez N, Castellón EA, Mejía N, de Herreros AG, Contreras HR (2018) The transcriptional factor ZEB1 represses Syndecan 1 expression in prostate cancer. Sci Rep 8(1):11467. https://doi.org/10.1038/s41598-018-29829-1
Figiel S, Vasseur C, Bruyere F, Rozet F, Maheo K, Fromont G (2017) Clinical significance of epithelial-mesenchymal transition markers in prostate cancer. Hum Pathol 61:26–32. https://doi.org/10.1016/j.humpath.2016.10.013
Finke D, Heckmann MB, Frey N, Lehmann LH (2021) Cancer—a major cardiac comorbidity with implications on cardiovascular metabolism [mini review]. Front Physiol. https://doi.org/10.3389/fphys.2021.729713
Graham TR, Zhau HE, Odero-Marah VA, Osunkoya AO, Kimbro KS, Tighiouart M, O’Regan RM (2008) Insulin-like growth factor-I-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res 68(7):2479–2488. https://doi.org/10.1158/0008-5472.can-07-2559
Grozescu T, Popa F (2017) Prostate cancer between prognosis and adequate/proper therapy. J Med Life 10(1):5–12
Jędroszka D, Orzechowska M, Hamouz R, Górniak K, Bednarek AK (2017) Markers of epithelial-to-mesenchymal transition reflect tumor biology according to patient age and Gleason score in prostate cancer. PLoS ONE 12(12):e0188842–e0188842. https://doi.org/10.1371/journal.pone.0188842
Karihtala P, Auvinen P, Kauppila S, Haapasaari KM, Jukkola-Vuorinen A, Soini Y (2013) Vimentin, ZEB1 and Sip1 are up-regulated in triple-negative and basal-like breast cancers: association with an aggressive tumour phenotype. Breast Cancer Res Treat 138(1):81–90. https://doi.org/10.1007/s10549-013-2442-0
Kovacic JC, Dimmeler S, Harvey RP, Finkel T, Aikawa E, Krenning G, Baker AH (2019) Endothelial to mesenchymal transition in cardiovascular disease: JACC state-of-the-art review. JAAC 73(2):190–209. https://doi.org/10.1016/j.jacc.2018.09.089
Krebs AM, Mitschke J, Lasierra Losada M, Schmalhofer O, Boerries M, Busch H, Brabletz T (2017) The EMT-activator ZEB1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol 19(5):518–529. https://doi.org/10.1038/ncb3513
Li H, Zou J, Yu X-H, Ou X, Tang C-K (2021) Zinc finger E-box binding homeobox 1 and atherosclerosis: new insights and therapeutic potential. J Cell Physiol 236(6):4216–4230. https://doi.org/10.1002/jcp.30177
Liu Y, Lu X, Huang L, Wang W, Jiang G, Dean KC, Dean DC (2014) Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis. Nat Commun 5:5660. https://doi.org/10.1038/ncomms6660
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4):402–408. https://doi.org/10.1006/meth.2001.1262
Madany M, Thoma T, Edwards L (2018) The curious case of ZEB1. Discoveries 6:e86. https://doi.org/10.15190/d.2018.7
Marín-Aguilera M, Codony-Servat J, Reig Ò, Lozano JJ, Fernández PL, Pereira MV, Mellado B (2014) Epithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer. Mole Cancer Ther 13(5):1270–1284. https://doi.org/10.1158/1535-7163.mct-13-0775
Okugawa Y, Toiyama Y, Tanaka K, Matsusita K, Fujikawa H, Saigusa S, Kusunoki M (2012) Clinical significance of zinc finger E-box binding homeobox 1 (ZEB1) in human gastric cancer. J Surg Oncol 106(3):280–285. https://doi.org/10.1002/jso.22142
Orellana-Serradell O, Herrera D, Castellon E, Contreras H (2018) The transcription factor ZEB1 promotes an aggressive phenotype in prostate cancer cell lines. AJA 20(3):294–299. https://doi.org/10.4103/aja.aja_61_17
Orellana-Serradell O, Herrera D, Castellón EA, Contreras HR (2019) The transcription factor ZEB1 promotes chemoresistance in prostate cancer cell lines. AJA 21(5):460–467. https://doi.org/10.4103/aja.aja_1_19
Pérez G, López-Moncada F, Indo S, Torres MJ, Castellón EA, Contreras HR (2021) Knockdown of ZEB1 reverses cancer stem cell properties in prostate cancer cells. Oncol Rep 45(5):58. https://doi.org/10.3892/or.2021.8009
Prensner JR, Rubin MA, Wei JT, Chinnaiyan AM (2012) Beyond PSA: the next generation of prostate cancer biomarkers. Sci Transl Med 4(127):127–123. https://doi.org/10.1126/scitranslmed.3003180
Rawla P (2019) Epidemiology of prostate cancer. World J Oncol 10(2):63–89. https://doi.org/10.14740/wjon1191
Rebello RJ, Oing C, Knudsen KE, Loeb S, Johnson DC, Reiter RE, Bristow RG (2021) Prostate cancer. Nat Rev Dis Prim 7(1):9. https://doi.org/10.1038/s41572-020-00243-0
Ritch CR, Cookson MS (2016) Advances in the management of castration resistant prostate cancer. BMJ 355:i4405. https://doi.org/10.1136/bmj.i4405
Shah PP, Lockwood WW, Saurabh K, Kurlawala Z, Shannon SP, Waigel S, Beverly LJ (2015) Ubiquilin1 represses migration and epithelial-to-mesenchymal transition of human non-small cell lung cancer cells. Oncogene 34(13):1709–1717. https://doi.org/10.1038/onc.2014.97
Shen A, Zhang Y, Yang H, Xu R, Huang G (2012) Overexpression of ZEB1 relates to metastasis and invasion in osteosarcoma. J Surg Oncol 105(8):830–834. https://doi.org/10.1002/jso.23012
Siegel RL, Miller KD, Jemal A (2017) Cancer Statistics, 2017. CA Cancer J Clin 67(1):7–30. https://doi.org/10.3322/caac.21387
Singh M, Spoelstra NS, Jean A, Howe E, Torkko KC, Clark HR, Richer JK (2008) ZEB1 expression in type I vs type II endometrial cancers: a marker of aggressive disease. Mod Pathol 21(7):912–923. https://doi.org/10.1038/modpathol.2008.82
Spaderna S, Schmalhofer O, Wahlbuhl M, Dimmler A, Bauer K, Sultan A, Brabletz T (2008) The transcriptional repressor ZEB1 promotes metastasis and loss of cell polarity in cancer. Cancer Res 68(2):537–544. https://doi.org/10.1158/0008-5472.can-07-5682
Vasaikar SV, Deshmukh AP, den Hollander P, Addanki S, Kuburich NA, Kudaravalli S, Mani SA (2021) EMTome: a resource for pan-cancer analysis of epithelial-mesenchymal transition genes and signatures. Br J Cancer 124(1):259–269. https://doi.org/10.1038/s41416-020-01178-9
Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A, Brabletz T (2009) The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 11(12):1487–1495. https://doi.org/10.1038/ncb1998
Zhang Y, Xu L, Li A, Han X (2019) The roles of ZEB1 in tumorigenic progression and epigenetic modifications. Biomed Pharmacother 110:400–408. https://doi.org/10.1016/j.biopha.2018.11.112
Acknowledgements
The teamwork would like to express their thanks and gratitude to all the volunteers and their families for their participation and to acknowledge the support and help by the late Dr. Nidhal el ATI in the collection of patients ' databases.
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RS, JHL, and SO conceived and designed the study. RS, AH, and SR provided clinical samples. RS, JHL, RLH, and TM provided technical support. RS, SK, RJ, and AD collected clinical parameters. RS performed experiments. RS analyzed data. RS wrote the manuscript. RS, JHL, and SO revised the manuscript. All authors approved the final manuscript submitted for publication.
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This project was approved by a Charles Nicolle ethical committee, Tunis, Tunisia. Relevant protocols followed in our retrospective study were performed following guidelines and regulations of The Code of Ethics of the World Medical Association (Declaration of Helsinki).
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Said, R., Hernández-Losa, J., Jenni, R. et al. An insight into the diagnostic, prognostic, and taxanes resistance of double zinc finger and homeodomain factor’s expression in naïve prostate cancer. 3 Biotech 14, 106 (2024). https://doi.org/10.1007/s13205-024-03941-8
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DOI: https://doi.org/10.1007/s13205-024-03941-8