Journal of Kerman University of Medical Sciences

The Significant Suppression of miR-4521 and Up Regulation of FOXM1 Isoforms in Breast Cancer

Document Type : Original Article

Authors

Sahar Kargar 1
Shirin Shahbazi 1
Loabat Geranpayeh 2

1 Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

2 Department of Surgery, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran

https://doi.org/10.34172/jkmu.4082
Abstract
 Introduction: As a transcription factor, FOXM1 is elaborate in diverse aspects of cancer, such as proliferation, invasion as well as metastasis. Alternative splicing creates several FOXM1 isoforms, among which FOXM1b and FOXM1c are the key transcripts evaluated. Recently, FOXM1 was reported to be direct target of miR-4521, a microRNA with a possible tumor suppressor role. In this study alterations in miR-4521 expression and its association with FOXM1b and FOXM1c were investigated in ductal carcinoma of breast.
Methods: Gene expression was examined in 44 matched tumor and adjacent normal tissue samples, along with the MCF-7 cell line. By designing specific primers, the expression of two FOXM1 transcript variants and the miR-4521 gene, along with internal controls were calculated by quantitative Real-time PCR. The amplified fragments were checked via Sanger sequencing.
Results: The expression of FOXM1b and FOXM1c significantly increased in tumor tissues, emphasizing the oncogenic role of both transcript variants in breast cancer. The fold change in FOXM1b and FOXM1c were 4.62 and 3.12, respectively. miR-4521 was significantly down-regulated in tumors (fold change: 0.218), which validate the tumor suppressor effect. A decrease in miR-4521 expression had a statistically significant association with the increased expression of FOXM1b and FOXM1c (P = 0.000).
Conclusion: Targeting the FOXM1 transcription factor represents a promising approach to halt breast cancer progression. Our findings indicate that FOXM1b and FOXM1c might have a role in the progress of breast cancer, and miR-4521 could be a potential candidate for their suppression.

Keywords

Alternative splicing
MicroRNAs
Forkhead box protein M1
Carcinoma
Ductal
Subjects
  1. Krupczak-Hollis K, Wang X, Kalinichenko VV, Gusarova GA, Wang IC, Dennewitz MB, et al. The mouse forkhead box M1 transcription factor is essential for hepatoblast mitosis and development of intrahepatic bile ducts and vessels during liver morphogenesis. Dev Biol 2004;276(1):74-88. doi:10.1016/j. ydbio.2004.08.022
  2. Senfter D, Samadaei M, Mader RM, Gojo J, Peyrl A, Krupitza G, et al. High impact of miRNA-4521 on FOXM1 expression in medulloblastoma. Cell Death Dis 2019;10(10):696. doi:10.1038/s41419-019-1926-1
  3. Kuthethur R, Adiga D, Kandettu A, Jerome MS, Mallya S, Mumbrekar KD, et al. MiR-4521 perturbs FOXM1-mediated DNA damage response in breast cancer. Front Mol Biosci 2023;10:1131433. doi:10.3389/fmolb.2023.1131433
  4. Peake BF, Nahta R. Resistance to HER2-targeted therapies: a potential role for FOXM1. Breast Cancer Manag 2014;3(5):423- 31. doi:10.2217/bmt.14.33
  5. O’Regan RM, Nahta R. Targeting forkhead box M1 transcription factor in breast cancer. Biochem Pharmacol 2018;154:407-13. doi:10.1016/j.bcp.2018.05.019
  6. Guillen VS, Ziegler Y, Gopinath C, Kumar S, Dey P, Plotner BN, et al. Effective combination treatments for breast cancer inhibition by FOXM1 inhibitors with other targeted cancer drugs. Breast Cancer Res Treat 2023;198(3):607-21. doi:10.1007/s10549-023-06878-3
  7. Nakamura S, Hirano I, Okinaka K, Takemura T, Yokota D, Ono T, et al. The FOXM1 transcriptional factor promotes the proliferation of leukemia cells through modulation of cell cycle progression in acute myeloid leukemia. Carcinogenesis 2010;31(11):2012-21. doi:10.1093/carcin/bgq185
  8. Dibb M, Han N, Choudhury J, Hayes S, Valentine H, West C, et al. The FOXM1-PLK1 axis is commonly upregulated in oesophageal adenocarcinoma. Br J Cancer 2012;107(10):1766-75. doi:10.1038/bjc.2012.424
  9. Hamurcu Z, Ashour A, Kahraman N, Ozpolat B. FOXM1 regulates expression of eukaryotic elongation factor 2 kinase and promotes proliferation, invasion and tumorgenesis of human triple negative breast cancer cells. Oncotarget 2016;7(13):16619-35. doi:10.18632/oncotarget.7672
  10. Barger CJ, Branick C, Chee L, Karpf AR. Pan-cancer analyses reveal genomic features of FOXM1 overexpression in cancer. Cancers (Basel) 2019;11(2):251. doi:10.3390/ cancers11020251
  11. Kazemi A, Agha-Alinejad H, Alizadeh S, Shahbazi S, Amani- Shalamzari S. The effect of endurance training on miR- 155 expression, STAT3 gene expression, and interleukin 6 protein in mice with breast cancer. J Kerman Univ Med Sci 2013;21(6):42-52.
  1. Lam AK, Ngan AW, Leung MH, Kwok DC, Liu VW, Chan DW, et al. FOXM1b, which is present at elevated levels in cancer cells, has a greater transforming potential than FOXM1c. Front Oncol 2013;3:11. doi:10.3389/fonc.2013.00011
  2. Wierstra I, Alves J. Transcription factor FOXM1c is repressed by RB and activated by cyclin D1/Cdk4. Biol Chem 2006;387(7):949-62. doi:10.1515/bc.2006.119
  3. Kopanja D, Chand V, O’Brien E, Mukhopadhyay NK, Zappia MP, Islam A, et al. Transcriptional repression by FOXM1 suppresses tumor differentiation and promotes metastasis of breast cancer. Cancer Res 2022;82(13):2458-71. doi:10.1158/0008-5472.Can-22-0410
  4. Ma RY, Tong TH, Cheung AM, Tsang AC, Leung WY, Yao KM. Raf/MEK/MAPK signaling stimulates the nuclear translocation and transactivating activity of FOXM1c. J Cell Sci 2005;118(Pt 4):795-806. doi:10.1242/jcs.01657
  5. Sun B, Cong D, Chen K, Bai Y, Li J. Prognostic value of microRNA-4521 in non-small cell lung cancer and its regulatory effect on tumor progression. Open Med (Wars) 2021;16(1):1150-9. doi:10.1515/med-2021-0312
  6. Feng X, Yan N, Sun W, Zheng S, Jiang S, Wang J, et al. miR- 4521-FAM129A axial regulation on ccRCC progression through TIMP-1/MMP2/MMP9 and MDM2/p53/Bcl2/Bax pathways. Cell Death Discov 2019;5:89. doi:10.1038/ s41420-019-0167-5
  7. Ayesha M, Majid A, Zhao D, Greenaway FT, Yan N, Liu Q, et al. MiR-4521 plays a tumor repressive role in growth and metastasis of hepatocarcinoma cells by suppressing phosphorylation of FAK/AKT pathway via targeting FAM129A. J Adv Res 2022;36:147-61. doi:10.1016/j.jare.2021.05.003
  8. Li C, Peng S, Tang C. Retracted article: microRNA-4521 targets hepatoma up-regulated protein (HURP) to inhibit the malignant progression of breast cancer. Bioengineered 2024;15(1):1996016. doi:10.1080/21655979.2021.1996016
  9. Park YY, Jung SY, Jennings NB, Rodriguez-Aguayo C, Peng G, Lee SR, et al. FOXM1 mediates Dox resistance in breast cancer by enhancing DNA repair. Carcinogenesis 2012;33(10):1843- 53. doi:10.1093/carcin/bgs167
  10. Nestal de Moraes G, Delbue D, Silva KL, Robaina MC, Khongkow P, Gomes AR, et al. FOXM1 targets XIAP and survivin to modulate breast cancer survival and chemoresistance. Cell Signal 2015;27(12):2496-505. doi:10.1016/j.cellsig.2015.09.013
  11. Khongkow P, Gomes AR, Gong C, Man EP, Tsang JW, Zhao F, et al. Paclitaxel targets FOXM1 to regulate KIF20A in mitotic catastrophe and breast cancer paclitaxel resistance. Oncogene 2016;35(8):990-1002. doi:10.1038/onc.2015.152
  12. Ulhaka K, Kanokwiroon K, Khongkow M, Bissanum R, Khunpitak T, Khongkow P. The anticancer effects of FDI-6, a FOXM1 inhibitor, on triple negative breast cancer. Int J Mol Sci 2021;22(13):6685. doi:10.3390/ijms22136685

 

 

Journal of Kerman University of Medical Sciences
Volume 33
Pages 1-6

Home

Editorial Board

Guide for Authors

Submit Manuscript

Guide for Reviewers

Contact Us