Skip to main content

Advertisement

SpringerLink
Log in

Expression of the circulating and the tissue microRNAs after surgery, chemotherapy, and radiotherapy in mice mammary tumor

  • Original Article
  • Published:
Tumor Biology

Abstract

The expression of microRNAs (miRNAs), as novel biomarkers, is subject to change in many cancers. Therefore, the overall profile of miRNAs can be used for detection of cancer type, response to therapies, pathological variables, and other factors related to the disease. In this study, to evaluate miRNA expression associated with the tumor progression and response to treatment, 60 BALB/c mice received subcutaneous injections of 4T1 cells. The study includes ten groups: one group as control, six groups were euthanized at different time points to assess the role of miRNA expression in the tumor progression, and three groups received chemotherapy, radiotherapy, and surgery to evaluate miRNA expression in response to treatment. MicroRNAs were extracted from the breast tumor and the plasma samples, and their relative expressions were quantified using qRT-PCR. MiR-155 expression was increased in the plasma in the early weeks after the cell injection but decreased in the plasma after surgery and radiotherapy and also in tumor samples after chemotherapy and radiotherapy. MiR-10b expression was increased in the late weeks both in the plasma and the tumor and was decreased in the plasma after radiotherapy and surgery and in the tumor after radiotherapy. MiR-21 expression was increased in the plasma and the tumor tissue during the disease progression at the third and the fourth weeks following tumor induction but was decreased in the plasma in all the therapy groups. Interestingly, miR-125a showed a significant decrease during the tumor progression, and its expression was increased after the treatment. Our results showed that the candidate miRNAs could be divided into two groups of oncomiRs and tumor suppressor miR based on their deregulation after tumor growth and treatments. It seems that the oncomiRs in the plasma can be an ideal noninvasive candidate biomarker for the early detection of breast cancer and also for following the response of the common therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.

    Article  CAS  PubMed  Google Scholar 

  2. Fritz S, Hackert T, Hinz U, Hartwig W, Büchler M, Werner J. Role of serum carbohydrate antigen 19-9 and carcinoembryonic antigen in distinguishing between benign and invasive intraductal papillary mucinous neoplasm of the pancreas. Br J Surg. 2011;98(1):104–10.

    Article  CAS  PubMed  Google Scholar 

  3. Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11(6):426–37.

    Article  CAS  PubMed  Google Scholar 

  4. Si M, Zhu S, Wu H, Lu Z, Wu F, Mo Y. miR-21-mediated tumor growth. Oncogene. 2007;26(19):2799–803.

    Article  CAS  PubMed  Google Scholar 

  5. Zhu S, Si M-L, Wu H, Mo Y-Y. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1. J Biol Chem. 2007;282(19):14328–36.

    Article  CAS  PubMed  Google Scholar 

  6. Roldo C, Missiaglia E, Hagan JP, Falconi M, Capelli P, Bersani S, et al. MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J Clin Oncol. 2006;24(29):4677–84.

    Article  CAS  PubMed  Google Scholar 

  7. Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH. Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem. 2008;283(2):1026–33.

    Article  CAS  PubMed  Google Scholar 

  8. Iorio MV, Casalini P, Tagliabue E, Ménard S, Croce CM. MicroRNA profiling as a tool to understand prognosis, therapy response and resistance in breast cancer. Eur J Cancer. 2008;44(18):2753–9.

    Article  CAS  PubMed  Google Scholar 

  9. Ma L, Reinhardt F, Pan E, Soutschek J, Bhat B, Marcusson EG, et al. Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model. Nat Biotechnol. 2010;28(4):341–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Scott GK, Goga A, Bhaumik D, Berger CE, Sullivan CS, Benz CC. Coordinate suppression of ERBB2 and ERBB3 by enforced expression of micro-RNA miR-125a or miR-125b. J Biol Chem. 2007;282(2):1479–86.

    Article  CAS  PubMed  Google Scholar 

  11. Jiang S, Zhang H-W, Lu M-H, He X-H, Li Y, Gu H, et al. MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Res. 2010;70(8):3119–27.

    Article  CAS  PubMed  Google Scholar 

  12. Isanejad A, Alizadeh AM, Shalamzari SA, Khodayari H, Khodayari S, Khori V, et al. MicroRNA-206, let-7a and microRNA-21 pathways involved in the anti-angiogenesis effects of the interval exercise training and hormone therapy in breast cancer. Life Sci. 2016;151:30–40.

    Article  CAS  PubMed  Google Scholar 

  13. Iorio MV, Ferracin M, Liu C-G, Veronese A, Spizzo R, Sabbioni S, et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 2005;65(16):7065–70.

    Article  CAS  PubMed  Google Scholar 

  14. Alizadeh AM, Shiri S, Farsinejad S. Metastasis review: from bench to bedside. Tumour Biol. 2014;35(9):8483–523.

    Article  PubMed  Google Scholar 

  15. Sharbati-Tehrani S, Kutz-Lohroff B, Bergbauer R, Scholven J, Einspanier R. miR-Q: a novel quantitative RT-PCR approach for the expression profiling of small RNA molecules such as miRNAs in a complex sample. BMC Mol Biol. 2008;9(1):1–13.

    Article  Google Scholar 

  16. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci. 2008;105(30):10513–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang F, Hou J, Jin W, Li J, Yue Y, Jin H, et al. Increased circulating microRNA-155 as a potential biomarker for breast cancer screening: a meta-analysis. Molecules. 2014;19(5):6282–93.

    Article  PubMed  Google Scholar 

  18. Farhangi B, Alizadeh AM, Khodayari H, Khodayari S, Dehghan MJ, Khori V, et al. Protective effects of dendrosomal curcumin on an animal metastatic breast tumor. Eur J Pharmacol. 2015;758:188–96.

    Article  CAS  PubMed  Google Scholar 

  19. Alizadeh AM, Sadeghizadeh M, Najafi F, Ardestani SK, Erfani-Moghadam V, Khaniki M, et al. Encapsulation of curcumin in diblock copolymer micelles for cancer therapy. BioMed research international. 2015;2015:824746.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wang W. Radiotherapy in the management of early breast cancer. Journal of medical radiation sciences. 2013;60(1):40–6.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Hemmati M, Abbaspour A, Alizadeh A, Khaniki M, Amanzadeh A, Mohagheghi M, et al. Rat xenograft chondrosarcoma development by human tissue fragment. Exp Oncol. 2011;33(1):52–4.

    CAS  PubMed  Google Scholar 

  22. Mohsenikia M, Alizadeh AM, Khodayari S, Khodayari H, Karimi A, Zamani M, et al. The protective and therapeutic effects of alpha-solanine on mice breast cancer. Eur J Pharmacol. 2013;718(1):1–9.

    Article  CAS  PubMed  Google Scholar 

  23. Khori V, Shalamzari SA, Isanejad A, Alizadeh AM, Alizadeh S, Khodayari S, et al. Effects of exercise training together with tamoxifen in reducing mammary tumor burden in mice: possible underlying pathway of miR-21. Eur J Pharmacol. 2015;765:179–87.

    Article  CAS  PubMed  Google Scholar 

  24. Costinean S, Zanesi N, Pekarsky Y, Tili E, Volinia S, Heerema N, et al. Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in Eμ-miR155 transgenic mice. Proc Natl Acad Sci. 2006;103(18):7024–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sun Y, Wang M, Lin G, Sun S, Li X, Qi J, et al. Serum microRNA-155 as a potential biomarker to track disease in breast cancer. PLoS One. 2012;7(10):e47003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. O’Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, Chaudhuri AA, et al. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity. 2010;33(4):607–19.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Haque I, Banerjee S, Mehta S, De A, Majumder M, Mayo MS, et al. Cysteine-rich 61-connective tissue growth factor-nephroblastoma-overexpressed 5 (CCN5)/Wnt-1-induced signaling protein-2 (WISP-2) regulates microRNA-10b via hypoxia-inducible factor-1α-TWIST signaling networks in human breast cancer cells. J Biol Chem. 2011;286(50):43475–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature. 2007;449(7163):682–8.

    Article  CAS  PubMed  Google Scholar 

  29. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117(7):927–39.

    Article  CAS  PubMed  Google Scholar 

  30. Ibrahim SA, Yip GW, Stock C, Pan JW, Neubauer C, Poeter M, et al. Targeting of syndecan-1 by microRNA miR-10b promotes breast cancer cell motility and invasiveness via a Rho-GTPase- and E-cadherin-dependent mechanism. Int J Cancer. 2012;131(6):E884–96.

    Article  CAS  PubMed  Google Scholar 

  31. Anastasov N, Höfig I, Vasconcellos IG, Rappl K, Braselmann H, Ludyga N, et al. Radiation resistance due to high expression of miR-21 and G2/M checkpoint arrest in breast cancer cells. Radiat Oncol. 2012;7(1):1.

    Article  Google Scholar 

  32. Fujita S, Ito T, Mizutani T, Minoguchi S, Yamamichi N, Sakurai K, et al. miR-21 gene expression triggered by AP-1 is sustained through a double-negative feedback mechanism. J Mol Biol. 2008;378(3):492–504.

    Article  CAS  PubMed  Google Scholar 

  33. Yan L-X, Huang X-F, Shao Q, Huang M-Y, Deng L, Wu Q-L, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Volinia S, Calin GA, Liu C-G, Ambs S, Cimmino A, Petrocca F, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A. 2006;103(7):2257–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Asangani I, Rasheed S, Nikolova D, Leupold J, Colburn N, Post S, et al. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 2008;27(15):2128–36.

    Article  CAS  PubMed  Google Scholar 

  36. Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005;65(14):6029–33.

    Article  CAS  PubMed  Google Scholar 

  37. Hu HY, Li KP, Wang XJ, Liu Y, Lu ZG, Dong RH, et al. Set9, NF-κB, and microRNA-21 mediate berberine-induced apoptosis of human multiple myeloma cells. Acta Pharmacol Sin. 2013;34(1):157–66.

  38. Hu N, Wang C, Han X-Y, He L-J, Tang Z-Z, Giffen C, et al. Evaluation of BRCA2 in the genetic susceptibility of familial esophageal cancer. Oncogene. 2004;23(3):852–8.

    Article  CAS  PubMed  Google Scholar 

  39. Gao J, Zhang Q, Xu J, Guo L, Li X. Clinical significance of serum miR-21 in breast cancer compared with CA153 and CEA. Chin J Cancer Res. 2013;25(6):743–8.

    PubMed  PubMed Central  Google Scholar 

  40. Zhao D, Tu Y, Wan L, Bu L, Huang T, Sun X, et al. In vivo monitoring of angiogenesis inhibition via down-regulation of mir-21 in a VEGFR2-luc murine breast cancer model using bioluminescent imaging. PLoS One. 2013;8(8):e71472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chaudhry MA, Sachdeva H, Omaruddin RA. Radiation-induced micro-RNA modulation in glioblastoma cells differing in DNA-repair pathways. DNA Cell Biol. 2010;29(9):553–61.

    Article  CAS  PubMed  Google Scholar 

  42. Chaudhry MA. Real-time PCR analysis of micro-RNA expression in ionizing radiation-treated cells. Cancer Biother Radiopharm. 2009;24(1):49–56.

    Article  CAS  PubMed  Google Scholar 

  43. García-Becerra R, Santos N, Diaz L, Camacho J. Mechanisms of resistance to endocrine therapy in breast cancer: focus on signaling pathways, mirnas and genetically based resistance. Int J Mol Sci. 2013;14(1):108–45.

  44. Toiyama Y, Takahashi M, Hur K, Nagasaka T, Tanaka K, Inoue Y, et al. Serum miR-21 as a diagnostic and prognostic biomarker in colorectal cancer. J Natl Cancer Inst. 2013;105(12):849–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sun Y-M, Lin K-Y, Chen Y-Q. Diverse functions of miR-125 family in different cell contexts. J Hematol Oncol. 2013;6(6).

  46. Bi Q, Tang S, Xia L, Du R, Fan R, Gao L, et al. Ectopic expression of MiR-125a inhibits the proliferation and metastasis of hepatocellular carcinoma by targeting MMP11 and VEGF. PLoS One. 2012;7(6):e40169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wagner-Ecker M, Schwager C, Wirkner U, Abdollahi A, Huber PE. MicroRNA expression after ionizing radiation in human endothelial cells. Radiation Oncology. 2010; 5(25).

  48. Zhao B-S, Liu S-G, Wang T-Y, Ji Y-H, Qi B, Tao Y-P, et al. Screening of microRNA in patients with esophageal cancer at same tumor node metastasis stage with different prognoses. Asian Pac J Cancer Prev. 2013;14(1):139–43.

    Article  PubMed  Google Scholar 

  49. Kardeh S, Ashkani-Esfahani S, Alizadeh AM. Paradoxical action of reactive oxygen species in creation and therapy of cancer. Eur J Pharmacol. 2014;735:150–68.

    Article  CAS  PubMed  Google Scholar 

  50. Farsinejad S, Gheisary Z, Samani SE, Alizadeh AM. Mitochondrial targeted peptides for cancer therapy. Tumor Biol. 2015;36(8):5715–25.

    Article  CAS  Google Scholar 

  51. Simone NL, Soule BP, Ly D, Saleh AD, Savage JE, DeGraff W, et al. Ionizing radiation-induced oxidative stress alters miRNA expression. PLoS One. 2009;4(7):e6377.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Zhao L, Bode AM, Cao Y, Dong Z. Regulatory mechanisms and clinical perspectives of miRNA in tumor radiosensitivity. Carcinogenesis. 2012;33(11):2220–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang L, Yuan C, Lv K, Xie S, Fu P, Liu X, et al. Lin28 mediates radiation resistance of breast cancer cells via regulation of caspase, H2A.X and Let-7 signaling. PLoS One. 2013;8(6):e67373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Marvaso G, Barone A, Amodio N. Emerging role of microRNAs in breast cancer radiotherapy. RNA & DISEASE. 2015;2(4):e786.

    Google Scholar 

  55. Cellini F, Morganti AG, Genovesi D, Silvestris N, Valentini V. Role of microRNA in response to ionizing radiations: evidences and potential impact on clinical practice for radiotherapy. Molecules. 2014;19(4):5379–401.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was funded by the Tehran University of Medical Sciences (Grant Number 23797).

Author information

Authors and Affiliations

  1. Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran

    Sadaf Farsinejad, Mahdi Rahaie, Mohammad Mir-Derikvand & Zohre Gheisary

  2. Cancer Research Center, Tehran University of Medical Sciences, Tehran, 1419733141, Iran

    Ali Mohammad Alizadeh & Solmaz Khalighfard

  3. Radiation Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Hassan Nosrati

Authors
  1. Sadaf Farsinejad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahdi Rahaie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ali Mohammad Alizadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammad Mir-Derikvand
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zohre Gheisary
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hassan Nosrati
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Solmaz Khalighfard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ali Mohammad Alizadeh.

Ethics declarations

Conflicts of interest

None

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Farsinejad, S., Rahaie, M., Alizadeh, A.M. et al. Expression of the circulating and the tissue microRNAs after surgery, chemotherapy, and radiotherapy in mice mammary tumor. Tumor Biol. 37, 14225–14234 (2016). https://doi.org/10.1007/s13277-016-5292-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5292-7

Keywords

Search

Navigation