Journal of Gastrointestinal Surgery

, Volume 21, Issue 1, pp 94–105 | Cite as

Restitution of Tumor Suppressor MicroRNA-145 Using Magnetic Nanoformulation for Pancreatic Cancer Therapy

  • Saini Setua
  • Sheema Khan
  • Murali M. Yallapu
  • Stephen W. Behrman
  • Mohammed Sikander
  • Shabia Shabir Khan
  • Meena Jaggi
  • Subhash C. Chauhan
2016 SSAT Plenary Presentation

Abstract

Introduction

The functional significance of lost microRNAs has been reported in several human malignancies, including pancreatic cancer (PC). Our prior work has identified microRNA-145 (miR-145) as a tumor suppressor microRNA (miRNA) in pancreatic cancer. The restoration of miR-145 downregulates a number of oncogenes including mucin MUC13, a transmembrane glycoprotein that is aberrantly expressed in pancreatic cancer, thus efficiently inhibiting tumor growth in mice. However, lack of an effective tumor-specific delivery system remains an unmet clinical challenge for successful translation of microRNAs.

Methods

We developed a miRNA-145-based magnetic nanoparticle formulation (miR-145-MNPF) and assessed its anti-cancer efficacy. Physico-chemical characterization (dynamic light scattering (DLS), transmission electron microscopy (TEM) and miR-binding efficiency), cellular internalization (Prussian blue and confocal microscopy), miR-145 restitution potential (quantitative reverse-transcription PCR (qRT-PCR), and anti-cancer efficacy (proliferation, colony formation, cell migration, cell invasion assays) of this formulation were performed using clinically relevant pancreatic cancer cell lines (HPAF-II, AsPC-1).

Results

miR-145-MNPF exhibited optimal particle size and zeta potential which effectively internalized and restituted miR-145 in pancreatic cancer cells. miR-145 re-expression resulted in downregulation of MUC13, HER2, pAKT, and inhibition of cell proliferation, clonogenicity, migration, and invasion of pancreatic cancer cells.

Conclusions

miR-145-MNPF is an efficient system for miR-145 delivery and restitution in pancreas cancer that may offer a potential therapeutic treatment for PC either alone or in conjunction with conventional treatment.

Keywords

Magnetic nanoparticle miR-145 Pancreatic cancer Therapeutics Nanotherapies 

References

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: A Cancer Journal for Clinicians. 2016;66(1):7–30. doi:10.3322/caac.21332.CrossRefGoogle Scholar
  2. 2.
    Wu Y, Crawford M, Mao Y, Lee RJ, Davis IC, Elton TS et al. Therapeutic Delivery of MicroRNA-29b by Cationic Lipoplexes for Lung Cancer. Mol Ther Nucleic Acids. 2013;2:e84. doi:10.1038/mtna.2013.14.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Chen C-Z. MicroRNAs as Oncogenes and Tumor Suppressors. New England Journal of Medicine. 2005;353(17):1768–71. doi:doi:10.1056/NEJMp058190.
  4. 4.
    Khan S, Ebeling MC, Zaman MS, Sikander M, Yallapu MM, Chauhan N et al. MicroRNA-145 targets MUC13 and suppresses growth and invasion of pancreatic cancer. Oncotarget. 2014;5(17):7599–609.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Sureban SM, May R, Qu D, Weygant N, Chandrakesan P, Ali N et al. DCLK1 Regulates Pluripotency and Angiogenic Factors via microRNA-Dependent Mechanisms in Pancreatic Cancer. PLoS ONE. 2013;8(9):e73940. doi:10.1371/journal.pone.0073940.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Kent OA, Chivukula RR, Mullendore M, Wentzel EA, Feldmann G, Lee KH et al. Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway. Genes & Development. 2010;24(24):2754–9. doi:10.1101/gad.1950610.CrossRefGoogle Scholar
  7. 7.
    Gao S, Wang P, Hua Y, Xi H, Meng Z, Liu T et al. ROR functions as a ceRNA to regulate Nanog expression by sponging miR-145 and predicts poor prognosis in pancreatic cancer. Oncotarget. 2016;7(2):1608–18.PubMedGoogle Scholar
  8. 8.
    Yallapu MM, Othman SF, Curtis ET, Gupta BK, Jaggi M, Chauhan SC. Multi-functional magnetic nanoparticles for magnetic resonance imaging and cancer therapy. Biomaterials. 2011;32(7):1890–905.CrossRefPubMedGoogle Scholar
  9. 9.
    Yallapu MM, Ebeling MC, Khan S, Sundram V, Chauhan N, Gupta BK et al. Novel curcumin-loaded magnetic nanoparticles for pancreatic cancer treatment. Molecular cancer therapeutics. 2013;12(8):1471–80. doi:10.1158/1535-7163.mct-12-1227.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Yallapu MM, Othman SF, Curtis ET, Bauer NA, Chauhan N, Kumar D et al. Curcumin-loaded magnetic nanoparticles for breast cancer therapeutics and imaging applications. International Journal of Nanomedicine. 2012;7:1761–79. doi:10.2147/ijn.s29290.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Ibrahim AF, Weirauch U, Thomas M, Grünweller A, Hartmann RK, Aigner A. MiRNA replacement therapy through PEI-mediated in vivo delivery of miR-145 or miR-33a in colon carcinoma. Cancer Research. 2011. doi:10.1158/0008-5472.can-10-4645.PubMedGoogle Scholar
  12. 12.
    Patnaik S, Gupta KC. Novel polyethylenimine-derived nanoparticles for in vivo gene delivery. Expert Opinion on Drug Delivery. 2013;10(2):215–28. doi:10.1517/17425247.2013.744964.CrossRefPubMedGoogle Scholar
  13. 13.
    Liang GF, Zhu YL, Sun B, Hu FH, Tian T, Li SC et al. PLGA-based gene delivering nanoparticle enhance suppression effect of miRNA in HePG2 cells. Nanoscale Research Letters. 2011;6:447. doi:10.1186/1556-276x-6-447.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Khan S, Ebeling MC, Chauhan N, Thompson PA, Gara RK, Ganju A et al. Ormeloxifene suppresses desmoplasia and enhances sensitivity of gemcitabine in pancreatic cancer. Cancer Res. 2015;75(11):2292–304. doi:10.1158/0008-5472.CAN-14-2397.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Khan S, Chauhan N, Yallapu MM, Ebeling MC, Balakrishna S, Ellis RT et al. Nanoparticle formulation of ormeloxifene for pancreatic cancer. Biomaterials. 2015;53:731–43. doi:10.1016/j.biomaterials.2015.02.082.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Chauhan SC, Vannatta K, Ebeling MC, Vinayek N, Watanabe A, Pandey KK et al. Expression and functions of transmembrane mucin MUC13 in ovarian cancer. Cancer Res. 2009;69(3):765–74. doi:10.1158/0008-5472.CAN-08-0587.CrossRefPubMedGoogle Scholar
  17. 17.
    Jaggi M, Rao PS, Smith DJ, Wheelock MJ, Johnson KR, Hemstreet GP et al. E-cadherin phosphorylation by protein kinase D1/protein kinase C{mu} is associated with altered cellular aggregation and motility in prostate cancer. Cancer Res. 2005;65(2):483–92.PubMedGoogle Scholar
  18. 18.
    Liang W, Gong H, Yin D, Lu S, Fu Q. High-Molecular-Weight Polyethyleneimine Conjuncted Pluronic for Gene Transfer Agents. Chemical and Pharmaceutical Bulletin. 2011;59(9):1094–101. doi:10.1248/cpb.59.1094.CrossRefPubMedGoogle Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2016

Authors and Affiliations

  • Saini Setua
    • 1
  • Sheema Khan
    • 1
  • Murali M. Yallapu
    • 1
  • Stephen W. Behrman
    • 2
  • Mohammed Sikander
    • 1
  • Shabia Shabir Khan
    • 3
  • Meena Jaggi
    • 1
  • Subhash C. Chauhan
    • 1
  1. 1.Department of Pharmaceutical Sciences and Center for Cancer ResearchUniversity of Tennessee Health Science CenterMemphisUSA
  2. 2.Department of SurgeryUniversity of Tennessee Health Science CenterMemphisUSA
  3. 3.Department of Computer ScienceUniversity of KashmirSrinagarIndia

Personalised recommendations