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Dysregulated RUNX1 Predicts Poor Prognosis by Mediating Epithelialmesenchymal Transition in Cervical Cancer

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Abstract

Objective

Runt-related transcription factor 1 (RUNX1) has been proven to be over-expressed and vital in many malignancies. However, its role in cervical cancer is still unclear.

Methods

Some online databases (Oncomine, GEPIA, UALCAN, LinkedOmics, and others) were used to explore the expression level, prognostic significance, and gene mutation characteristics of RUNX1 in cervical cancer. The protein levels of RUNX1 in cervical cancer were measured by immunohistochemistry (IHC). The functional changes of cervical cancer cells were measured in vitro after decreasing RUNX1.

Results

Bioinformatic results revealed that RUNX1 was upregulated in cervical cancer compared to normal tissues. Moreover, over-expression of RUNX1 was significantly correlated with cervical cancer patients’ clinical parameters (e.g., individual cancer stages, patients’ age, nodal metastasis status, and others). Meanwhile, functional enrichment analysis of RUNX1-related genes indicated that RUNX1 was mainly involved in the epithelial-mesenchymal transition (EMT) process in cervical cancer. Furthermore, RUNX1 may be upregulated by hsamiR-616-5p and hsa-miR-766 identified by miRDB, TargetScan, and miRWalk. Finally, RUNX1 was upregulated in cervical cancer compared to normal tissues by IHC in collected cervical cancer samples. The invasion and migration abilities of cervical cancer cells were significantly reduced by repressing EMT after knocking down RUNX1 in vitro.

Conclusion

RUNX1 was highly expressed in cervical cancer, and upregulated RUNX1 could significantly promote the invasive abilities of cervical cancer cells by inducing EMT. Therefore, RUNX1 may be a potential biomarker for early diagnosis and targeted therapy of cervical cancer.

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References

  1. Hull R, Mbele M, Makhafola T, et al. Cervical cancer in low and middle-income countries. Oncol Lett, 2020,20(3):2058–2074

    Article  Google Scholar 

  2. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018,68(6):394–424

    Article  Google Scholar 

  3. Bao HL, Liu YN, Wang LJ, et al. Analysis on mortality of cervical cancer and its temporal trend in women in China, 2006–2012. Zhonghua Liu Xing Bing Xue Za Zhi (Chinese), 2017,38(1):58–64

    Google Scholar 

  4. Lei J, Ploner A, Elfström KM, et al. HPV Vaccination and the Risk of Invasive Cervical Cancer. N Engl J Med, 2020,383(14):1340–1348

    Article  Google Scholar 

  5. Buskwofie A, David-West G, Clare CA. A Review of Cervical Cancer: Incidence and Disparities. J Natl Med Assoc, 2020,112(2):229–232

    Google Scholar 

  6. Chopra S, Gupta M, Mathew A, et al. Locally advanced cervical cancer: A study of 5-year outcomes. Indian J Cancer, 2018,55(1):45–49

    Article  Google Scholar 

  7. Salunkhe R, Chopra S, Kulkarni S, et al. Outcomes of locally advanced cervical cancer presenting with obstructive uropathy: An institutional audit. Indian J Cancer, 2020,57(4):416–422

    Google Scholar 

  8. Kumar L, Harish P, Malik PS, et al. Chemotherapy and targeted therapy in the management of cervical cancer. Curr Probl Cancer, 2018,42(2):120–128

    Article  Google Scholar 

  9. Gadducci A, Cosio S. Neoadjuvant Chemotherapy in Locally Advanced Cervical Cancer: Review of the Literature and Perspectives of Clinical Research. Anticancer Res, 2020,40(9):4819–4828

    Article  Google Scholar 

  10. Cibula D, Pötter R, Planchamp F, et al. The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology guidelines for the management of patients with cervical cancer. Radiother Oncol, 2018,127(3):404–416

    Article  Google Scholar 

  11. Westerveld H, Nesvacil N, Fokdal L, et al. Definitive radiotherapy with image-guided adaptive brachytherapy for primary vaginal cancer. Lancet Oncol, 2020,21(3):e157–e167

    Article  Google Scholar 

  12. Feng CH, Mell LK, Sharabi AB, et al. Immunotherapy With Radiotherapy and Chemoradiotherapy for Cervical Cancer. Semin Radiat Oncol, 2020,30(4):273–280

    Article  Google Scholar 

  13. Chung HC, Ros W, Delord JP, et al. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol, 2019,37(17):1470–1478

    Article  Google Scholar 

  14. Stevanović S, Draper LM, Langhan MM, et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J Clin Oncol, 2015,33(14):1543–1550

    Article  Google Scholar 

  15. Frenel JS, Le Tourneau C, O’Neil B, et al. Safety and Efficacy of Pembrolizumab in Advanced, Programmed Death Ligand 1-Positive Cervical Cancer: Results From the Phase Ib KEYNOTE-028 Trial. J Clin Oncol, 2017,35(36):4035–4041

    Article  Google Scholar 

  16. Simon L, Spinella JF, Yao CY, et al. High frequency of germline RUNX1 mutations in patients with RUNX1-mutated AML. Blood, 2020,135(21):1882–1886

    Article  Google Scholar 

  17. Choi A, Illendula A, Pulikkan JA, et al. RUNX1 is required for oncogenic Myb and Myc enhancer activity in T-cell acute lymphoblastic leukemia. Blood, 2017,130(15):1722–1733

    Article  Google Scholar 

  18. Tang CY, Wu M, Zhao D, et al. Runx1 is a central regulator of osteogenesis for bone homeostasis by orchestrating BMP and WNT signaling pathways. PLoS Genet, 2021,17(1):e1009233

    Article  Google Scholar 

  19. Tang CY, Chen W, Luo Y, et al. Runx1 up-regulates chondrocyte to osteoblast lineage commitment and promotes bone formation by enhancing both chond-rogenesis and osteogenesis. Biochem J, 2020,477(13): 2421–2438

    Article  Google Scholar 

  20. Li Q, Lai Q, He C, et al. RUNX1 promotes tumour metastasis by activating the Wnt/β-catenin signalling pathway and EMT in colorectal cancer. J Exp Clin Cancer Res, 2019,38(1):334

    Article  Google Scholar 

  21. Zhou T, Luo M, Cai W, et al. Runt-Related Transcription Factor 1 (RUNX1) Promotes TGF-β-Induced Renal Tubular Epithelial-to-Mesenchymal Transition (EMT) and Renal Fibrosis through the PI3K Subunit p110δ. EBioMedicine, 2018,31:217–225

    Article  Google Scholar 

  22. Rhodes DR, Yu J, Shanker K, et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia, 2004,6(1):1–6

    Article  Google Scholar 

  23. Tang Z, Li C, Kang B, et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res, 2017,45(W1): W98–W102

    Article  Google Scholar 

  24. Chandrashekar DS, Bashel B, Balasubramanya SAH, et al. UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses. Neoplasia, 2017,19(8):649–658

    Article  Google Scholar 

  25. Liu CJ, Hu FF, Xia MX, et al. GSCALite: a web server for gene set cancer analysis. Bioinformatics, 2018,34(21):3771–3772

    Article  Google Scholar 

  26. Pathan M, Keerthikumar S, Ang CS, et al. FunRich: An open access standalone functional enrichment and interaction network analysis tool. Proteomics, 2015,15(15):2597–2601

    Article  Google Scholar 

  27. Vasaikar SV, Straub P, Wang J, et al. LinkedOmics: analyzing multi-omics data within and across 32 cancer types. Nucleic Acids Res, 2017,46(D1):D956–D963

    Article  Google Scholar 

  28. Hänzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics, 2013,14:7

    Article  Google Scholar 

  29. Yoshihara K, Shahmoradgoli M, Martínez E, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun, 2013,4:2612

    Article  Google Scholar 

  30. Sticht C, De La Torre C, Parveen A, et al. miRWalk: An online resource for prediction of microRNA binding sites. PLoS One, 2018,13(10):e0206239

    Article  Google Scholar 

  31. Du A, Zhao S, Wan L, et al. MicroRNA expression profile of human periodontal ligament cells under the influence of Porphyromonas gingivalis LPS. J Cell Mol Med, 2016,20(7):1329–1338

    Article  Google Scholar 

  32. Liu W, Wang X. Prediction of functional microRNA targets by integrative modeling of microRNA binding and target expression data. Genome Biol, 2019,20(1):18

    Article  Google Scholar 

  33. Agarwal V, Bell GW, Nam JW, et al. Predicting effective microRNA target sites in mammalian mRNAs. Elife, 2015,4:e05005

    Article  Google Scholar 

  34. Kagabu M, Nagasawa T, Sato C, et al. Immunotherapy for Uterine Cervical Cancer Using Checkpoint Inhibitors: Future Directions. Int J Mol Sci, 2020,21(7):2335

    Article  Google Scholar 

  35. Ventriglia J, Paciolla I, Pisano C, et al. Immunotherapy in ovarian, endometrial and cervical cancer: State of the art and future perspectives. Cancer Treat Rev, 2017,59:109–116

    Article  Google Scholar 

  36. Ferrall L, Lin KY, Roden RBS, et al. Cervical Cancer Immunotherapy: Facts and Hopes. Clin Cancer Res, 2021,27(18):4953–4973

    Article  Google Scholar 

  37. Wang L, Brugge JS, Janes KA. Intersection of FOXO- and RUNX1-mediated gene expression programs in single breast epithelial cells during morphogenesis and tumor progression. Proc Natl Acad Sci USA, 2011,108(40):E803–812

    Article  Google Scholar 

  38. Takayama K, Suzuki T, Tsutsumi S, et al. RUNX1, an androgen- and EZH2-regulated gene, has differential roles in AR-dependent and -independent prostate cancer. Oncotarget, 2015,6(4):2263–2276

    Article  Google Scholar 

  39. Liu C, Xu D, Xue B, et al. Upregulation of RUNX1 Suppresses Proliferation and Migration through Repressing VEGFA Expression in Hepatocellular Carcinoma. Pathol Oncol Res, 2020,26(2):1301–1311

    Article  Google Scholar 

  40. Miyagawa K, Sakakura C, Nakashima S, et al. Down-regulation of RUNX1, RUNX3 and CBFbeta in hepatocellular carcinomas in an early stage of hepatocarcinogenesis. Anticancer Res, 2006,26(5b): 3633–3643

    Google Scholar 

  41. Alonso-Alconada L, Muinelo-Romay L, Madissoo K, et al. Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer. Mol Cancer, 2014,13:223

    Article  Google Scholar 

  42. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol, 2014,15(3):178–196

    Article  Google Scholar 

  43. Nieto MA, Huang RY, Jackson RA, et al. EMT: 2016. Cell, 2016,166(1):21–45

    Article  Google Scholar 

  44. Kavanagh DP, Robinson J, Kalia N. Mesenchymal stem cell priming: fine-tuning adhesion and function. Stem Cell Rev Rep, 2014,10(4):587–599

    Article  Google Scholar 

  45. Jolly MK, Ware KE, Gilja S, et al. EMT and MET: necessary or permissive for metastasis? Mol Oncol, 2017,11(7):755–769

    Article  Google Scholar 

  46. Pastushenko I, Blanpain C. EMT Transition States during Tumor Progression and Metastasis. Trends Cell Biol, 2019,29(3):212–226

    Article  Google Scholar 

  47. Gonzalez-Avila G, Sommer B, Garcia-Hernandez AA, et al. Matrix Metalloproteinases’ Role in Tumor Microenvironment. Adv Exp Med Biol, 2020,1245:97–131

    Article  Google Scholar 

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Correspondence to Chang-sheng Yi, Xing-dang Liu or Ji-gang Yang.

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Zheng, Ll., Cai, L., Zhang, Xq. et al. Dysregulated RUNX1 Predicts Poor Prognosis by Mediating Epithelialmesenchymal Transition in Cervical Cancer. CURR MED SCI 42, 1285–1296 (2022). https://doi.org/10.1007/s11596-022-2661-x

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  • DOI: https://doi.org/10.1007/s11596-022-2661-x

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