Journal of Isfahan Medical School

Journal of Isfahan Medical School

Expression of miR-125 and MCL-1 and BCL-2 Anti-apoptotic Genes under the Influence of Valproic Acid Treatment in Breast Cancer Cell Lines

Document Type : Original Article (s)

Authors
Nastaran Injinari 1
Zeinab Amini-Farsani 2
Hossein Teimori 3
1 MSc Student,, Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
2 PhD in Molecular Genetics, Young Researchers and Elites Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
3 Associate Professor, Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
10.22122/jims.v37i542.12349
Abstract
Background: One of the causes of death through breast cancer is drug resistance and the anti-apoptotic activity of cancer cells. Epigenetic factors are involved in both of these processes. Micro RNAs (miRNAs) are epigenetic agents that accelerate the inappropriate expression of cancer. Valproic acid is a histone deacetylase inhibitor that has anticancer activity. The aim of this study was to evaluate the effect of valproic acid on miR-125b expression as one of the tumor suppressor miRNAs in breast cancer, and the expression of BCL-2 and MCL-1 anti-apoptotic genes as possible targets of miR-125b in MDA-MB-231 and MCF-7 cell lines.Methods: In this experimental study, MDA-MB-231 and MCF-7 cell lines were first cultured in optimal conditions. Cell viability was measured at different concentrations of valproic acid at 48 and 72 hours using MTT assay. The expression of miR-125b and BCL-2 and MCL-1 genes was analyzed using real-time polymerase chain reaction (PCR). The data were analyzed using one-way ANOVA test.Findings: Valproic acid significantly decreased the viability of both cell lines in dose- and time-dependent manner. It also led to a significant increase in miR-125b in both cell lines (P < 0.010). In MCF-7 cells, this drug led to a significant decrease in BCL-2 and MCL-1 genes (P < 0.001). But the difference in these two genes in MDA-MB-231 treated cells was not significant compared to the control group (P > 0.050).Conclusion: Valproic acid may be suggested as a profitable option in cancer research, through its involvement in epigenetic processes, and its influence on the expression of BCL-2 and MCL-1 genes.
Keywords
Apoptosis
Breast Cancer
miRNA
Valproic acid
  1. Pasculli B, Barbano R, Parrella P. Epigenetics of breast cancer: Biology and clinical implication in the era of precision medicine. Semin Cancer Biol 2018; 51: 22-35.
  2. Zhou X, Li Z, Wang X, Jiang G, Shan C, Liu S. Metabolomics reveals the effect of valproic acid on MCF-7 and MDA-MB-231 cells. Xenobiotica 2019; 1-9. . [Epub ahead of print].
  3. Peschansky VJ, Wahlestedt C. Non-coding RNAs as direct and indirect modulators of epigenetic regulation. Epigenetics 2014; 9(1): 3-12.
  4. Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006; 6(1): 38-51.
  5. Ruan K, Fang X, Ouyang G. MicroRNAs: Novel regulators in the hallmarks of human cancer. Cancer Lett 2009; 285(2): 116-26.
  6. Stahlhut Espinosa CE, Slack FJ. The role of microRNAs in cancer. Yale J Biol Med 2006; 79(3-4): 131-40.
  7. Sun YM, Lin KY, Chen YQ. Diverse functions of miR-125 family in different cell contexts. J Hematol Oncol 2013; 6: 6.
  8. Gerl R, Vaux DL. Apoptosis in the development and treatment of cancer. Carcinogenesis 2005; 26(2): 263-70.
  9. Campbell KJ, Dhayade S, Ferrari N, Sims AH, Johnson E, Mason SM, et al. MCL-1 is a prognostic indicator and drug target in breast cancer. Cell Death Dis 2018; 9(2): 19.
  10. Hird AW, Tron AE. Recent advances in the development of Mcl-1 inhibitors for cancer therapy. Pharmacol Ther 2019; 198: 59-67.
  11. Zarella MD, Heintzelman RC, Popnikolov NK, Garcia FU. BCL-2 expression aids in the immunohistochemical prediction of the Oncotype DX breast cancer recurrence score. BMC Clin Pathol 2018; 18: 14.
  12. Sajadpoor Z, Amini-Farsani Z, Teimori H, Shamsara M, Sangtarash MH, Ghasemi-Dehkordi P, et al. Valproic acid promotes apoptosis and cisplatin sensitivity through downregulation of H19 noncoding RNA in ovarian A2780 cells. Appl Biochem Biotechnol 2018; 185(4): 1132-44.
  13. Terranova-Barberio M, Roca MS, Zotti AI, Leone A, Bruzzese F, Vitagliano C, et al. Valproic acid potentiates the anticancer activity of capecitabine in vitro and in vivo in breast cancer models via induction of thymidine phosphorylase expression. Oncotarget 2016; 7(7): 7715-31.
  14. Aztopal N, Erkisa M, Erturk E, Ulukaya E, Tokullugil AH, Ari F. Valproic acid, a histone deacetylase inhibitor, induces apoptosis in breast cancer stem cells. Chem Biol Interact 2018; 280: 51-8.
  15. Paik WH, Ryu JK, Jeong KS, Park JM, Song BJ, Lee SH, et al. Clobenpropit enhances anti-tumor effect of gemcitabine in pancreatic cancer. World J Gastroenterol 2014; 20(26): 8545-57.
  16. Nohara K, Yokoyama Y, Kano K. The important role of caspase-10 in sodium butyrate-induced apoptosis. Kobe J Med Sci 2007; 53(5): 265-73.
  17. Kawakami H, Huang S, Pal K, Dutta SK, Mukhopadhyay D, Sinicrope FA. Mutant BRAF Upregulates MCL-1 to confer apoptosis resistance that is reversed by MCL-1 antagonism and cobimetinib in colorectal cancer. Mol Cancer Ther 2016; 15(12): 3015-27.
  18. Yarmohamadi A, Asadi J, Gharaei R, Mirzadeh M, Khoshnazar A. Valproic acid, a histone deacetylase inhibitor, enhances radiosensitivity in breast cancer cell line. Journal of Radiation and Cancer Research 2018; 9: 86.
  19. Kawagoe R, Kawagoe H, Sano K. Valproic acid induces apoptosis in human leukemia cells by stimulating both caspase-dependent and -independent apoptotic signaling pathways. Leuk Res 2002; 26(5): 495-502.
  20. Willimott S, Wagner SD. miR-125b and miR-155 contribute to BCL2 repression and proliferation in response to CD40 ligand (CD154) in human leukemic B-cells. J Biol Chem 2012; 287(4): 2608-17.
  21. Lin T, Ren Q, Zuo W, Jia R, Xie L, Lin R, et al. Valproic acid exhibits anti-tumor activity selectively against EGFR/ErbB2/ErbB3-coexpressing pancreatic cancer via induction of ErbB family members-targeting microRNAs. J Exp Clin Cancer Res 2019; 38(1): 150.
  22. Campbell KJ, Tait SWG. Targeting BCL-2 regulated apoptosis in cancer. Open Biol 2018; 8(5).
  23. Young AI, Law AM, Castillo L, Chong S, Cullen HD, Koehler M, et al. MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib. Breast Cancer Res 2016; 18(1): 125.
  24. Gilardini Montani MS, Granato M, Santoni C, Del PP, Merendino N, D'Orazi G, et al. Histone deacetylase inhibitors VPA and TSA induce apoptosis and autophagy in pancreatic cancer cells. Cell Oncol (Dordr) 2017; 40(2): 167-80.
  25. Cohen AL, Soldi R, Zhang H, Gustafson AM, Wilcox R, Welm BE, et al. A pharmacogenomic method for individualized prediction of drug sensitivity. Mol Syst Biol 2011; 7: 513.
  26. Holliday DL, Speirs V. Choosing the right cell line for breast cancer research. Breast Cancer Res 2011; 13(4): 215.
Journal of Isfahan Medical School
Volume 37, Issue 542 - Serial Number 542
July and August 2019
Pages 1061-1067

  • Receive Date 06 October 2019
  • Accept Date 06 April 2022