Document Type : Original Article(s)

Authors

1 Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

2 Anatomy Department, Tehran University of Medical Sciences, Tehran, Iran

3 Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran

4 Department of Pathology, Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

10.30476/mejc.2024.102811.2110

Abstract

Background: Bladder cancer (BCa) accounts for the fourth most common cancer among men. Eukaryote translation initiation factor 4E (eIF4E) and its regulatory binding protein (4E-BP1) abnormal expression have been identified in numerous cancers. Therefore, we hypothesized and examined the existence of a connection between eIF4E and 4E-BP1 dysregulation and urothelial cancer (UC) in human subjects by employing more sensitive protein and gene expression experiments in both superficial and muscle-invasive UC.
Method: In this case-control study, the eIF4E and 4E-BP1 mRNA and protein levels were assessed in snap-frozen tissue samples of normal (n = 23), superficial (n = 38) and muscle invasive (n = 29) UC by immunohistochemical staining, quantitative real-time polymerase chain reaction and western blot. A comparison of different groups was carried out by Mann–Whitney U and Kruskal–Wallis tests using Graph Pad prism version 9. P < 0.05 were considered as significant.
Results: In addition to elevated expression for both eIF4E and 4E-BP1 in the UC group, we also considered upregulated patterns in both superficial and invasive UC as compared with the control group. An upregulated pattern was predominant in superficial group. Moreover, we observed diminished expression of eIF4E and 4E-BP1 in high-grade tissues of both superficial and invasive subjects compared with low-grade ones (P < 0.05).
Conclusion: The present data indicates a possible link between decreased 4E-BP1 expression and high-grade UC that might be associated with expression of cancer promoting genes. Whilst eIF4E may play a role in low grade UC.

Highlights

Mohammad Naji (Google Scholar)

Farzaneh Sharifiaghdas (Google Scholar)

Keywords

Main Subjects

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination, and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.30476/mejc.2024.102811.2110

  1. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48. doi: 10.3322/caac.21763. PMID: 36633525.
  2. Luzha J, Nass N, Czapiewski P, Schroeder N, Kalinski T, Schostak M, et al. Expression of eukaryotic translation initiation factors in the urothelial carcinoma of the bladder. Anticancer Res. 2023;43(4):1437-48. doi: 10.21873/anticanres.16292. PMID: 36974813.
  3. Dobruch J, Oszczudłowski M. Bladder cancer: Current challenges and future directions. Medicina (Kaunas). 2021;57(8):749. doi: 10.3390/medicina57080749. PMID: 34440955; PMCID: PMC8402079.
  4. Saginala K, Barsouk A, Aluru JS, Rawla P, Padala SA, Barsouk A. Epidemiology of bladder cancer. Med Sci (Basel). 2020;8(1):15. doi: 10.3390/medsci8010015. PMID: 32183076; PMCID: PMC7151633.
  5. Ashrafizadeh M, Zarrabi A, Karimi-Maleh H, Taheriazam A, Mirzaei S, Hashemi M, et al. (Nano)platforms in bladder cancer therapy: Challenges and opportunities. Bioeng Transl Med. 2022;8(1):e10353. doi: 10.1002/btm2.10353. PMID: 36684065; PMCID: PMC9842064.
  6. Lu C, Gao S, Zhang L, Shi X, Chen Y, Wei S, et al. Nuclear protein 1 expression is associated with PPARG in bladder transitional cell carcinoma. PPAR Res. 2023;2023:6797694. doi: 10.1155/2023/6797694. PMID: 37197716; PMCID: PMC10185424.
  7. Romagnoli A, D'Agostino M, Ardiccioni C, Maracci C, Motta S, La Teana A, et al. Control of the eIF4E activity: structural insights and pharmacological implications. Cell Mol Life Sci. 2021;78(21-22):6869-85. doi: 10.1007/s00018-021-03938-z. PMID: 34541613; PMCID: PMC8558276.
  8. Zhang L, Zhang Y, Zhang S, Qiu L, Zhang Y, Zhou Y, et al. Translational regulation by EIFs and RNA modifications in cancer. Genes. 2022;13(11):2050. doi: 10.3390/genes13112050. PMID: 36360287; PMCID: PMC9690228.
  9. Alain T, Morita M, Fonseca BD, Yanagiya A, Siddiqui N, Bhat M, et al. eIF4E/4E-BP ratio predicts the efficacy of mTOR targeted therapies. Cancer Res. 2012;72(24):6468-76. doi: 10.1158/0008-5472.CAN-12-2395. PMID: 23100465.
  10. De Benedetti A, Graff JR. eIF-4E expression and its role in malignancies and metastases. Oncogene. 2004;23(18):3189-99. doi: 10.1038/sj.onc.1207545. PMID: 15094768.
  11. Mamane Y, Petroulakis E, Rong L, Yoshida K, Ler LW, Sonenberg N. eIF4E–from translation to transformation. Oncogene. 2004;23(18):3172-9. doi: 10.1038/sj.onc.1207549. PMID: 15094766.
  12. Ghosh R, Samanta P, Sarkar R, Biswas S, Saha P, Hajra S, et al. Targeting HIF-1α by natural and synthetic compounds: A promising approach for anti-cancer therapeutics development. Molecules. 2022;27(16):5192. doi: 10.3390/molecules27165192. PMID: 36014432; PMCID: PMC9413992.
  13. Weber R. Translational control by eukaryotic initiation factor (eIF) 4E and 4G homologous proteins[dissertation]. Tübingen: Universität Tübingen; 2022. 315 p. doi: 10.15496/publikation-53118.
  14. Yang M, Lu Y, Piao W, Jin H. The translational regulation in mTOR pathway. Biomolecules. 2022;12(6):802. doi: 10.3390/biom12060802. PMID: 35740927; PMCID: PMC9221026.
  15. Masoud GN, Li W. HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B. 2015;5(5):378-89. doi: 10.1016/j.apsb.2015.05.007. PMID: 26579469; PMCID: PMC4629436.
  16. Park SJ, Lee TJ, Chang IH. Role of the mTOR pathway in the progression and recurrence of bladder cancer: An immunohistochemical tissue microarray study. Korean J Urol. 2011;52(7):466-73. doi: 10.4111/kju.2011.52.7.466. PMID: 21860767; PMCID: PMC3151634.
  17. Piserà A, Campo A, Campo S. Structure and functions of the translation initiation factor eIF4E and its role in cancer development and treatment. J Genet Genomics. 2018;45(1):13-24. doi: 10.1016/j.jgg.2018.01.003. PMID: 29396141.
  18. Chen L, Wang H. eIF4E is a critical regulator of human papillomavirus (HPV)-immortalized cervical epithelial (H8) cell growth induced by nicotine. Toxicology. 2019;419:1-10. doi: 10.1016/j.tox.2019.02.017. PMID: 30836163.
  19. Lu J, Zang H, Zheng H, Zhan Y, Yang Y, Zhang Y, et al. Overexpression of p-Akt, p-mTOR and p-eIF4E proteins associates with metastasis and unfavorable prognosis in non-small cell lung cancer. PLoS One. 2020;15(2):e0227768. doi: 10.1371/journal.pone.0227768. PMID: 32023262; PMCID: PMC7001968.
  20. Carroll M, Borden KL. The oncogene eIF4E: using biochemical insights to target cancer. J Interferon Cytokine Res. 2013;33(5):227-38. doi: 10.1089/jir.2012.0142. PMID: 23472659; PMCID: PMC3653383.
  21. Jana S, Deo R, Hough RP, Liu Y, Horn JL, Wright JL, et al. mRNA translation is a therapeutic vulnerability necessary for bladder epithelial transformation. JCI Insight. 2021;6(11):e144920. doi: 10.1172/jci.insight.144920. PMID: 34032633; PMCID: PMC8262354.
  22. Chi BH, Kim SJ, Seo HK, Seo HH, Lee SJ, Kwon JK, et al. P70S6K and Elf4E dual inhibition is essential to control bladder tumor growth and progression in orthotopic mouse non-muscle invasive bladder tumor model. J Korean Med Sci. 2015;30(3):308-16. doi: 10.3346/jkms.2015.30.3.308. PMID: 25729255; PMCID: PMC4330487.
  23. Kyou Kwon J, Kim SJ, Hoon Kim J, Mee Lee K, Ho Chang I. Dual inhibition by S6K1 and Elf4E is essential for controlling cellular growth and invasion in bladder cancer. Urol Oncol. 2014;32(1):51.e27-35. doi: 10.1016/j.urolonc.2013.08.005. PMID: 24239466.
  24. Crew JP, Fuggle S, Bicknell R, Cranston DW, de Benedetti A, Harris AL. Eukaryotic initiation factor-4E in superficial and muscle invasive bladder cancer and its correlation with vascular endothelial growth factor expression and tumour progression. Br J Cancer. 2000;82(1):161-6. doi: 10.1054/bjoc.1999.0894. PMID: 10638984; PMCID: PMC2363195.
  25. Furic L, Rong L, Larsson O, Koumakpayi IH, Yoshida K, Brueschke A, et al. eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression. Proc Natl Acad Sci U S A. 2010;107(32):14134-9. doi: 10.1073/pnas.1005320107. PMID: 20679199; PMCID: PMC2922605.
  26. Robichaud N, del Rincon SV, Huor B, Alain T, Petruccelli LA, Hearnden J, et al. Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3. Oncogene. 2015;34(16):2032-42. doi: 10.1038/onc.2014.146. PMID: 24909168; PMCID: PMC4978545.
  27. Chen YT, Tsai HP, Wu CC, Wang JY, Chai CY. Eukaryotic translation initiation factor 4E (eIF-4E) expressions are associated with poor prognosis in colorectal adenocarcinoma. Pathol Res Pract. 2017;213(5):490-5. doi: 10.1016/j.prp.2017.02.004. PMID: 28242042.
  28. Heikkinen T, Korpela T, Fagerholm R, Khan S, Aittomäki K, Heikkilä P, et al. Eukaryotic translation initiation factor 4E (eIF4E) expression is associated with breast cancer tumor phenotype and predicts survival after anthracycline chemotherapy treatment. Breast Cancer Res Treat. 2013;141(1):79-88. doi: 10.1007/s10549-013-2671-2. PMID: 23974830.
  29. Diab-Assaf M, Abou-Khouzam R, Saadallah-Zeidan N, Habib K, Bitar N, Karam W, et al. Expression of eukaryotic initiation factor 4E and 4E binding protein 1 in colorectal carcinogenesis. Int J Clin Exp Pathol. 2015;8(1):404-13. PMID: 25755728; PMCID: PMC4348849.
  30. Maracci C, Motta S, Romagnoli A, Costantino M, Perego P, Di Marino D. The mTOR/4E-BP1/eIF4E signalling pathway as a source of cancer drug targets. Curr Med Chem. 2022;29(20):3501-29. doi: 10.2174/0929867329666220224112042. PMID: 35209811.
  31. Fahmy M, Mansure JJ, Brimo F, Yafi FA, Segal R, Althunayan A, et al. Relevance of the mammalian target of rapamycin pathway in the prognosis of patients with high-risk non-muscle invasive bladder cancer. Hum Pathol. 2013;44(9):1766-72. doi: 10.1016/j.humpath.2012.11.026. PMID: 23623586.
  32. Kim SJ, Kim JH, Jung HS, Lee TJ, Lee KM, Chang IH. Phosphorylated p70S6K in noninvasive low-grade urothelial carcinoma of the bladder: correlation with tumor recurrence. Asian J Androl. 2014;16(4):611-7. doi: 10.4103/1008-682X.123675. Erratum in: Asian J Androl. 2014;16(4):656. PMID: 24625880; PMCID: PMC4104092.
  33. Schultz L, Albadine R, Hicks J, Jadallah S, DeMarzo AM, Chen YB, et al. Expression status and prognostic significance of mammalian target of rapamycin pathway members in urothelial carcinoma of urinary bladder after cystectomy. Cancer. 2010;116(23):5517-26. doi: 10.1002/cncr.25502. PMID: 20939013; PMCID: PMC3568488.
  34. Hernández-Prat A, Rodriguez-Vida A, Juanpere-Rodero N, Arpi O, Menéndez S, Soria-Jiménez L, et al. Novel oral mTORC1/2 inhibitor TAK-228 has synergistic antitumor effects when combined with paclitaxel or PI3Kα inhibitor TAK-117 in preclinical bladder cancer models. Mol Cancer Res. 2019;17(9):1931-44. doi: 10.1158/1541-7786.MCR-18-0923. PMID: 31160383.