THE SIGNIFICANCE OF THE EXPRESSION OF THE EPITHELIAL-MESENCHYMAL TRANSITION MARKER SNAIL1 AND ITS REGULATOR TGF-β1 IN THE PROGRESSION OF ENDOMETRIOID CARCINOMA OF THE ENDOMETRY


L.G. Buchynska1 , N.M. Glushchenko1, S.V. Nespryadko2, I.O. Marchenko1, N.P. Iurchenko1
1R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
2 National Cancer Institute, Kyiv, Ukraine

DOI: https://doi.org/10.15407/oncology.2023.03.194

 

Summary. Aim: to evaluate the features of the expression of the cytokine TGF-β1 and the transcription factor Snail1 in endometrial tumor cells, depending on the degree of differentiation and the level of spread of the malignant process. Object and methods: surgical material samples of 54 patients with endometrioid carcinoma of the endometrium (ECE) with the I–II stage of the disease (median age 59 years), which were examined using: morphological, immunohistochemical and statistical methods. Results: significantly higher expression of cytokine TGF-β1 and transcription factor Snail1 was shown in low-differentiated endometrial carcinomas that invade deeply into the myometrium, compared to tumors of a high and moderate degree of differentiation with shallow invasion into the myometrium. In endometrial tumors with high Snail1 expression, a significant decrease in the expression of the epithelial cell marker E-cadherin and an increase in the expression of the mesenchymal marker vimentin were found. It was established that high mRNA expression of the TGFB1 and SNAI1 genes correlates with a decrease in the 5-year survival time of patients with ECE (GEPIA2 database). Conclusions: the results of the study suggest that, associated with the epithelial-mesenchymal transition, TGF-β1 and Snail1 modulate certain morphofunctional characteristics of malignant endometrial neoplasms and participate in the formation of the aggressiveness of this form of cancer. The obtained data indicate a high probability of using Snail1 and TGF-β1 as prognostic markers of the course of the disease in patients with this oncological pathology.

 

References

  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics 2021. CA. Cancer J Clin 2021; 71: 7–33. doi: 10.3322/caac.21654.
  2. Fedorenko Z, Gulak L, Gorokh Ye, Ryzhov A, Soumkina O. Cancer in Ukraine, 2021-2022. Incidence, mortality, prevalence and other relevant statistics. Bul Nat Registry of Ukraine 2023; 24: 82 p. Available from: http://www.ncru.inf.ua
  3. Corr B, Cosgrove C, Spinosa D,Guntupalli S. Endometrial cancer: molecular classification and  future   treatments. BMJMED 2022; 1:e000152. doi:10.1136/bmjmed-2022-000152.
  4. Movchan OM, Svintsitskiy VS, Tsip NP, et al. Features of recurrence of endometrioid type endometrial cancer of I stage. Exp Oncol 2021; 43 (4): 365–69. doi: 10.32471/exp-oncology.2312-8852.vol-43-no 4.17052.
  5. Concin N, Matias-Guiu X, Ignace Vergote, et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer 2021; 31: 12–39.
  6. Hussein YR, Broaddus R, Weigelt B, et al. The genomic heterogeneity of FIGO grade 3 endometrioid carcinoma impacts diagnostic accuracy and reproducibility. Int J Gynecol Pathol 2016; 35:16–24.
  7. Murali R, Davidson B, Fadare O, et al. High-grade еndometrial сarcinomas: morphologic and іmmunohistochemical features, diagnostic challenges and recommendations. Int J Gynecol Patho. 2019 38 (Suppl 1): S40-S63.
  8. Francou A, Anderson KV. The epithelial-to-mesenchymal transition in development and cancer. Annu Rev Cancer Biol 2020; 4: 197-220: www.annualreviews.org.
  9. Škovierová H, Okajčeková T, Strnádel J, et al. Molecular regulation of epithelial‑to‑mesenchymal transition in tumorigenesis (Review). Int J Mol Med 2018; 41: 1187-200. doi:10.3892/ijmm.2017.3320.
  10. Ribatti D. Tamma R, Annese T. Epithelial-Mesenchymal Transition in Cancer: A Historical Overview. Transl Oncol 2020; 13: 100773. www.elsevier.com/locate/tranon.
  11. Ahmadi A, Najafi M, Farhood B, Mortezaee K. Transforming growth factor β signalling: Tumorigenesis and targeting for cancer therapy. J Cell Physiol. 2018; 1–15. doi.org/10.1002/jcp.27955.
  12. Zakrzewski PK. Canonical TGF Signaling and its contribution to endometrial cancer development and progression–underestimated target of anticancer strategies. J Cli. Med 2021;10: 3900. doi.org/10.3390/jcm10173900.
  13. Krögera C, Afeyana A, Mraz J et al. Acquisition of a hybrid E/M state is essential fortumorigenicity of basal breast cancer cells. PNAS 2019; 116: 7353-62. doi/10.1073/pnas.1907473116.
  14. Kang E, Seo J, Yoon H, Cho S. The post-translational regulation of epithelial–mesenchymal transition-inducing transcription factors in cancer metastasis. Int J Mol Sci 2021: 22: 3591. doi.org/10.3390/ijms22073591.
  15. Tang X, Sui X, Weng L, Liu Y. Snail1: linking tumor metastasis to immune evasion. Front Immunol 2021; 12: 724200. doi: 10.3389/fimmu.2021.724200.
  16. Chen H-Y, Chiang Y-F, Huang J-S,  et al. Isoliquiritigenin reverses epithelial-mesenchymal transition through modulation of the TGF-β/Smad signaling pathway in endometrial cancer. Cancers 2021; 13: 1236: doi.org/10.3390/cancers13061236.
  17. Sadłecki P, Jóźwicki J, Antosik P, Walentowicz-Sadłecka M. Expression of selected epithelial-mesenchymal transition transcription factors in endometrial cancer. Bio Med Res Intern 2020; ID: 4584250. doi.org/10.1155/2020/4584250.
  18. Florescu MM, Cretu OI, Muraru A, et al. Snail Immunoexpression in Endometrioid Endometrial Carcinomas.  Current Health Sciences J  2022;  48 (4): 2022: 393-397. doi: 10.12865/CHSJ.48.04.05.
  19. Buchynska LG, Naleskina LА, Nesina IP. Morphological characteristics and expression of adhesion markers in cells of low differentiated endometrial carcinoma. Exp Oncol 2019; 41(4): 335–41. doi: https://doi.org/10.32471/exp-oncology.2312-8852.vol-41-no-4.13965.
  20. 20. Abdul Basit Baba, Bilal Rah, Gh Rasool Bhat, et al. Transforming Growth Factor-Beta (TGF-β) Signaling in Cancer-A Betrayal Within. Front Pharmacol. 2022: 13: 791272. doi: 10.3389/fphar.2022.791272.
  21. 21. Ji L, Xu J, Liu J, et al. Mutant p53 Promotes Tumor Cell Malignancy by Both Positive and Negative Regulation of the Transforming Growth Factor β (TGF-β) Pathway. JBC 2015: 290 (18):11729-40.
  22. 22. Bertran E, Caja L, Navarro E, et al. Role of CXCR4/SDF-1 alpha in the migratory phenotype of hepatoma cells that have undergone epithelial-mesenchymal transition in response to the transforming growth factor-beta. Cell Signal. 2009; 21 (11):1595-606. doi: 10.1016/j.cellsig.2009.06.006.
  23. Buchynska LG, Movchan OM, Iurchenko NP. Expression of chemokine receptor cxcr4 on tumor cells and content of CXCL12+-fibroblasts in endometrioid carcinoma of the endometrium. Exp Оncol. 2021; 43 (2): 135-141. doi: 10.32471/exp-oncology.2312-8852.vol-43-no-2.16240.
  24. Stemmler MP, Eccles RL, Brabletz S, Brabletz T. Non-redundant functions of EMT transcription factors. Nat Cell Biol 2019; 21 (1): 102-112. doi: 10.1038/s41556-018-0196-y.
  25. Buchynska LG, Borykun TV, Iurchenko N.P., et al. Expression of microRNA in tumor cells of endmetrioid carcinoma of endometrium. Exp Oncol 2020; 42 (4): 289-94.
  26. Siemens H, Jackstadt R, Hünten S, et al. miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions. Cell Cycle. 2011; 10 (24): 4256-71. doi: 10.4161/cc.10.24.18552.
  27. Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017; 16 (3): 203-22. doi: 10.1038/nrd.2016.246.

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