miR-21 and miR-155 in the regulation of TGF-β1/SMAD signaling pathway of the line breast cancer cells with different metastatic potential
https://doi.org/10.17650/1994-4098-2015-11-3-15-21
Abstract
Breast cancer (ВС) is the most common form of cancer, leading to high mortality rates among women worldwide. Metastasis is the main cause of fatal outcomes in ВС. In this regard, of particular interest takes the study of molecular mechanisms of epithelial-mesenchymal transition (EMT). In the EMT processes involved in TGF-β1/SMAD-signaling pathway through the regulation of which can affect the processes of metastasis in ВС.
In this study we have analyzed changes of mRNA expression of the mRNA SMADs, miR-21, and miR-155 of the tumor ВС cells with different metastatic potential MCF-7, BT-474, ZR-75-1. High expression of miR-21 was detected in all the tumor cell lines (MCF-7, ZR-75-1 and BT-474). In the ВС cell lines, the expression level of miR-155 was significantly lower than that of miR-21. Analysis of mRNA expression has clearly shown impairments of intracellular mechanisms of regulation of SMAD2, SMAD4, SMAD7 in ВС.
Investigated the correlation of expression of miR-21 and miR-155 regulation of SMADs in TGF-β1/SMAD signaling pathway in three carcinomas lines of the human breast with different metastatic potential (MCF-7, ZR-75-1, BT-474). A significant inverse correlation was observed between SMAD4 and miR-155 in MCF-7 cells. Inverse correlation between the expression of SMAD2, SMAD4, SMAD7 and miR-155; miR21 was found in the BT-474 cells.
The results obtained in this study showed that miR-21 and miR-155 regulate activity of several genes SMAD2, SMAD4, SMAD7 in the tumor cell ZR-75-1 and on some genes they exhibited a cumulative effect. It should be noted that the miR-155 and miR-21 in various degrees influenced the expression of SMAD2, SMAD4, SMAD7, blocking the work of these genes and, thereby exacerbating the progression and degree of malignancy of ВС cells human; in some cases their effects on individual genes were cumulative.
About the Authors
Z. N. Nikiphorova
N.N. Blokhin Russian Cancer Research Center; 24 Kashirskoe Shosse, Moscow, 115201, Russia
Russian Federation
Russian Federation
I. A. Kudryavtsev
N.N. Blokhin Russian Cancer Research Center; 24 Kashirskoe Shosse, Moscow, 115201, Russia
Russian Federation
Russian Federation
V. Е. Shevchenko
N.N. Blokhin Russian Cancer Research Center; 24 Kashirskoe Shosse, Moscow, 115201, Russia
Russian Federation
Russian Federation
References
1. Greenlee R.T., Murray T., Bolden S., Wingo P.A. Cancer statistics. CA Cancer J Clin 2000;50(1):7–33.
2. Zavadil J., Haley J., Kalluri R. et al. Epithelial-mesenchymal transition. Cancer Res 2008;68(23):9574–7.
3. Sørlie T., Perou C.M., Tibshirani R. et al. Gene expression patterns of breast carcinomasdistinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 2001;98(18):10869–74.
4. Rysman E., Brusselmans K., Scheys K. et al. De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation. Cancer Res 2010;70(20):8117–26.
5. Hugo H., Ackland M.L., Blick T. et al. Epithelial-mesenchymal and mesenchymalepithelial transitions in carcinoma progression. J Cell Physiol 2007;213(2):374–83.
6. Petersen M., Pardali E., van der Horst G. et al. Smad2 and Smad3 have opposing roles in breast cancer bone metastasis by differentially affecting tumor angiogenesis. Oncogene 2010;29(9):1351–61.
7. Pardali K., Moustakas A. Actions of TGFbeta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta 2007;1775(1):21–62.
8. Tang J., Ahmad A., Sarkar F.H. et al. The role of microRNAs in breast cancer migration, invasion and metastasis. Int J Mol Sci 2012;13(10):13414–37.
9. Sundqvist A., Ten Dijke P., van Dam H. et al. Key signaling nodes in mammary gland development and cancer: Smad signal integration in epithelial cell plasticity. Breast Cancer Res 2012;14(1):204.
10. Wu Y., Zhou B.P. New insights of epithelial-mesenchymal transition in cancer metastasis. Acta Biochim Biophys Sin 2008;40(7):643–50.
11. Sun Y., Wang M., Lin G. et al. Serum microRNA-155 as a potential biomarker to track disease in breast cancer. PLoS One 2012;7(10):e47003.
12. Yan L.X., Huang X.F., Shao Q. et al. MicroRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. RNA 2008;14(11):2348–60.
13. Zheng S.R. Clinical significance of miR155 expression in breast cancer and effects of miR-155 ASO on cell viability and apoptosis. Oncol Rep 2012;27(4):1149–55.
14. Stolfi C., Marafini I., De Simone et al. The dual role of Smad7 in the control of cancer growth and metastasis. Int J Mol Sci 2013;14(12):23774–90.
15. Aigner A. MicroRNAs (miRNAs) in cancer invasion and metastasis: therapeutic approaches based on metastasis-related miRNAs. J Mol Med (Berl) 2011;89(5): 445–57.
16. Chen L., Li Y., Fu Y. et al. Role of deregulated microRNAs in breast cancer progression using FFPE tissue. PLoS One 2013;8(1):e54213.
17. Zhu S., Wu H., Wu F. et al. MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res 2008;18(3):350–9.
18. Han M., Liu M., Wang Y. et al. Reexpression of miR-21 contributes to migration and invasion by inducing epithelialmesenchymal transition consistent with cancer stem cell characteristics in MCF-7 cells. Mol Cell Biochem 2012;363(1–2):427–36.
19. Lu Z., Ye Y., Jiao D. et al. miR-155 and miR-31 are differentially expressed in breast cancer patients and are correlated with the estrogen receptor and progesterone receptor status. Oncol Lett 2012;4(5):1027–32
20. Li Q., Zhang D., Wang Y. et al. MiR-21/ Smad7 signaling determines TGF-β1-induced CAF formation. Sci Rep 2013;3:2038.
21. Kong W., Yang H., He L. et al. MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA. Mol Cell Biol 2008;28:6773–84.
22. Subik K., Lee J.F., Baxter L. et al.The expression patterns of ER, PR, HER-2, CK5/6, EGFR, Ki-67 and AR by immunohistochemical analysis in breast cancer cell lines. Breast Cancer (Auckl) 2010;4:35–41.
23. Liang Y., Benakanakere I., Besch-Williford C. et al. Synthetic progestins induce growth and metastasis of BT-474 human breast cancer xenografts in nude mice. Menopause 2010;17(5):1040–7.
24. http://www.lgcstandards-atcc.org/.
25. Lattrich C., Stegerer A., Häring J. et al. Estrogen receptor β agonists affect growth and gene expression of human breast cancer cell lines. Steroids 2013;78(2): 195–202.
Review
For citations:
Nikiphorova Z.N., Kudryavtsev I.A., Shevchenko V.Е. miR-21 and miR-155 in the regulation of TGF-β1/SMAD signaling pathway of the line breast cancer cells with different metastatic potential. Tumors of female reproductive system. 2015;11(3):15-21. (In Russ.) https://doi.org/10.17650/1994-4098-2015-11-3-15-21
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