Advertisement

Tumor Biology

, Volume 35, Issue 3, pp 2335–2341 | Cite as

Regulation of onco and tumor suppressor MiRNAs by mTORC1 inhibitor PRP-1 in human chondrosarcoma

  • Karina A. Galoian
  • Toumy Guettouche
  • Biju Issac
  • Amir Qureshi
  • H. T. Temple
Research Article

Abstract

Metastatic chondrosarcoma of mesenchymal origin is the second most common bone malignancy and does not respond either to chemotherapy or radiation; therefore, the search for new therapies is relevant and urgent. This study aimed to reveal the comparative analysis of miRNAs and their targets in human JJ012 chondrosarcoma cell line between control and experimental samples, treated with mTORC1 inhibitor, cytostatic antiproliferative proline-rich polypeptide (PRP-1). Examination of tumor-specific microRNA expression profiles has revealed widespread deregulation of these molecules in diverse cancers. It was reported that microRNAs can function as novel biomarkers for disease diagnostics and therapy, as well as a novel class of oncogenes and tumor suppressor genes. mTORC 1 inhibitor PRP-1 caused significant upregulation of tumor suppressors, such as miR20a, miR125b, and miR192; and downregulation of onco miRNAs, miR509-3p, miR589, miR490-3p, miR 550 in human chondrosarcoma JJ012 cell line.

Keywords

Chondrosarcoma MiRNA mTORC1 inhibitor PRP-1 

Notes

Acknowledgments

The study was financially supported by the University of Miami Tissue Bank research account. We would like to thank Yoslalyma Cardentey, Loida Navarro, and Kathy Slosek from the University of Miami Oncogenomics Core Facility for their help and expertise.

Conflicts of interest

None

References

  1. 1.
    Mirra J. Bone tumors. Philadelphia: Lea and Febiger; 1989.Google Scholar
  2. 2.
    Frassica FJ, Unni KK, Beabout JW, Sim FH. Dedifferentiated chondrosarcoma. A report of the clinicopathological features and treatment of seventy-eight cases. J Bone Joint Surg Am. 1986;68:1197–205.PubMedGoogle Scholar
  3. 3.
    Schrage YM, Briaire-de Bruijn IH, de Miranda NF, van Oosterwijk J, Taminiau AH, van Wezel T, et al. Kinome profiling of chondrosarcoma reveals Src-pathway activity and dasatinib as option for treatment. Cancer Res. 2009;69:6216.PubMedCrossRefGoogle Scholar
  4. 4.
    Meyn III MA, Schreiner SJ, Dumitrescu TP, Gerard J, Nau GJ, Smithgall TE. Src family kinase activity is required for murine embryonic stem cell growth and differentiation. Mol Pharmacol. 2005;68:1320–30.PubMedCrossRefGoogle Scholar
  5. 5.
    Sakamoto A et al. H-ras oncogene mutation in dedifferentiated chondrosarcoma: polymerase chain reaction-restriction fragment length polymorph analysis. Mol Pathol. 2001;14(4):343–9.CrossRefGoogle Scholar
  6. 6.
    Galoian K, Scully S, McNamara G, Flynn P, Galoyan A. Antitumorigenic effect of brain proline rich polypeptide-1 in human chondrosarcoma. Neurochem Res. 2009;34(12):2117–21.PubMedCrossRefGoogle Scholar
  7. 7.
    Galoian K, Temple TH, Galoyan A. Cytostatic effect of the hypothalamic cytokine PRP-1 is mediated by mTOR and cMyc inhibition in high grade chondrosarcoma. Neurochem Res. 2011;36:812–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Galoian KA, Temple TH, Galoyan A. Cytostatic effect of novel mTOR inhibitor, PRP-1 (galarmin) in MDA 231 (ER-) breast carcinoma cell line. PRP-1 inhibits mesenchymal tumors. Tumour Biol. 2011;32(4):745–51.PubMedCrossRefGoogle Scholar
  9. 9.
    Galoian KA, Temple HT, Galoyan AA. mTORC1 inhibition and ECM–cell adhesion-independent drug resistance via PI3K–AKT and PI3K–RAS–MAPK feedback loops. Tumour Biol. 2012;33(3):885–90.PubMedCrossRefGoogle Scholar
  10. 10.
    Galoyan AA, Aprikyan VS. A new hypothalamic polypeptide is a regulator of myelopoiesis. Neurochem Res. 2002;27(4):305–12.PubMedCrossRefGoogle Scholar
  11. 11.
    Jin W, Yun C, Jeong J, Park Y, Lee HD, Kim SJ. c-Src is required for tropomyosin receptor kinase C (TrkC)-induced activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. J Biol Chem. 2008;283(3):1391–400.PubMedCrossRefGoogle Scholar
  12. 12.
    Carracedo A, Baselga J, Pandolfi PP. Deconstructing feedback-signaling networks to improve anticancer therapy with mTORC1 inhibitors. Cell Cycle. 2008;7(24):3805–9.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008;118(9):3065–74.PubMedCentralPubMedGoogle Scholar
  14. 14.
    Grant S. Cotargeting survival signaling pathways in cancer. J Clin Investig. 2008;118(9):3003–6.PubMedCentralPubMedGoogle Scholar
  15. 15.
    Thornton TM, Pedraza-Alva G, Deng B, Wood CD, Aronshtam A, Clements JL, et al. Phosphorylation by p38 MAPK as an alternative pathway for GSK3β inactivation. Science. 2008;320(5876):667–70.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Karni R et al. Active Src elevates the expression of beta-catenin by enhancement of cap-dependent translation. Mol Cell Biol. 2005;25(12):5032–9.CrossRefGoogle Scholar
  17. 17.
    Drakaki A, Iliopoulos D. MicroRNA gene networks in oncogenesis. Curr Genomics. 2009;10(1):35.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Portnoy V, Huang V, Place RF, Li LC. Small RNA and transcriptional upregulation. Wiley Interdiscip Rev RNA. 2011;2(5):748–60.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A. 2004;101:2999–3004.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Hatziapostolou M, Polytarchou C, Iliopoulos D. miRNAs link metabolic reprogramming to oncogenesis. Trends Endocrinol Metab. 2013;24(7):361–73.PubMedCrossRefGoogle Scholar
  21. 21.
    Dweep H, Sticht C, Pandey P, Gretz N. miRWalk - database: prediction of possible miRNA binding sites by "walking" the genes of three genomes. J Biomed Inform. 2011;44:839–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Elkayam E, Kuhn CD, Tocilj A, Astrid D, Haase AD, Greene EM, et al. The structure of human argonaute-2in complex with miR-20a. Cell. 2012;150(1):100–10.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Sun YM, Lin KY, Chen YQ. Diverse functions of miR-125 family in different cell contexts. J Hematol Oncol. 2013;6:6.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Liu LH, Li H, Li JP, Zhong H, Zhang HC, Chen J, et al. miR-125b suppresses the proliferation and migration of osteosarcoma cells through down-regulation of STAT3. Biochem Biophys Res Commun. 2011;416(1–2):31–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Georges SA, Biery MC, Kim SY, Schelter JM, Guo J, Chang AN, et al. Coordinated regulation of cell cycle transcripts by p53-inducible microRNAs, miR-192 and miR-215. Cancer Res. 2008;68(24):10105–12.PubMedCrossRefGoogle Scholar
  26. 26.
    Sudol M. Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product. Oncogene. 1994;9:2145–52.PubMedGoogle Scholar
  27. 27.
    Kobayashi T, Inoue T, Shimizu Y, Terada N, Maeno A, Kajita Y, et al. Activation of Rac1 is closely related to androgen-independent cell proliferation of prostate cancer cells both in vitro and in vivo. Mol Endocrinol. 2010;24(4):722–34.PubMedCrossRefGoogle Scholar
  28. 28.
    Chigrinova E, Mian M, Shen Y, Greiner TC, Chan WC, Vose JM, et al. Integrated profiling of diffuse large B-cell lymphoma with 7q gain. Br J Haematol. 2011;153(4):499–503.PubMedCrossRefGoogle Scholar
  29. 29.
    Zhang LY, Liu M, Li X, Tang H. miR-490-3p modulates cell growth and epithelial to mesenchymal transition of hepatocellular carcinoma cells by targeting endoplasmic reticulum-Golgi intermediate compartment protein 3 (ERGIC3). Biol Chem. 2013;288(6):4035–47.CrossRefGoogle Scholar
  30. 30.
    Barroso-del Jesus A, Romero-López C, Lucena-Aguilar G, Melen GJ, Sanchez L, Ligero G, et al. Embryonic stem cell-specific miR302-367 cluster: human gene structure and functional characterization of its core promoter. Mol Cell Biol. 2008;28(21):6609–19.CrossRefGoogle Scholar
  31. 31.
    Sakurai K, Furukawa C, Haraguchi T, Inada K, Shiogama K, Tagawa T, et al. MicroRNAs miR-199a-5p and -3p target the Brm subunit of SWI/SNF to generate a double-negative feedback loop in a variety of human cancers. Cancer Res. 2011;71(5):1680–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Tian Q, Liang L, Ding J, Zha R, Shi H, Wang Q, et al. MicroRNA-550a acts as a pro-metastatic gene and directly targets cytoplasmic polyadenylation element-binding protein 4 in hepatocellular carcinoma. PLoS One. 2012;7(11):e48958.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Gaedcke J, Grade M, Camps J, Søkilde R, Kaczkowski B, Schetter AJ, et al. The rectal cancer microRNAome—microRNA expression in rectal cancer and matched normal mucosa. Clin Cancer Res. 2012;18(18):4919–30.PubMedCrossRefGoogle Scholar
  34. 34.
    Wang D, Qiu C, Zhang H, Wang J, Cui Q, Yin Y. Human microRNA oncogenes and tumor suppressors show significantly different biological patterns: from functions to targets. PLoS One. 2010; 5(9): pii: e13067. doi:  10.1371/journal.pone.0013067
  35. 35.
    Doghman M, El Wakil A, Cardinaud B, Thomas E, Wang J, Zhao W, et al. Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors. Cancer Res. 2010;70(11):4666–75.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Oneyama C, Ikeda J, Okuzaki D, Suzuki K, Kanou T, Shintani Y, et al. MicroRNA-mediated downregulation of mTOR/FGFR3 controls tumor growth induced by Src-related oncogenic pathways. Oncogene. 2011;30:3489–350.PubMedCrossRefGoogle Scholar
  37. 37.
    Ma Y-C, Shi C, Zhang Y-N, Wang L-G, Liu H, Jia H-T, et al. The tyrosine kinase c-Src directly mediates growth factor-induced Notch-1 and furin interaction and Notch-1 activation in pancreatic cancer cells. PLOS One. 2012;7(3):e33414.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Zhai Q, Zhou L, Zhao C, Wan J, Yu Z, Guo X, et al. Identification of miR-508-3p and miR-509-3p that are associated with cell invasion and migration and involved in the apoptosis of renal cell carcinoma. PLoS One. 2010;5(10):e13735.CrossRefGoogle Scholar
  39. 39.
    Zhao H, Shen J, Medico L, Wang D, Ambrosone CB, Liu S. A pilot study of circulating miRNAs as potential biomarkers of early stage breast cancer. PLoS One. 2010;5(10):e13735.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Cameron ER, Neil JC. The Runx genes: lineage-specific oncogenes and tumor suppressors. Oncogene. 2004;23(24):4308–14.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Karina A. Galoian
    • 1
  • Toumy Guettouche
    • 2
  • Biju Issac
    • 3
  • Amir Qureshi
    • 4
  • H. T. Temple
    • 5
    • 6
  1. 1.Department of Orthopaedics, Miller School of MedicineUniversity of MiamiMiamiUSA
  2. 2.Center for Applied GenomicsChildren’s Hospital of PhiladelphiaPhiladelphiaUSA
  3. 3.Bioinformatics Core, Biostatistics and Bioinformatics Core, Division of Bioinformatics, Sylvester Comprehensive Cancer CenterUniversity of MiamiMiamiUSA
  4. 4.Department of Orthopaedic Surgery, Miller School of MedicineUniversity of MiamiMiamiUSA
  5. 5.Department of Orthopaedic Surgery, Miller School of MedicineUniversity of MiamiMiamiUSA
  6. 6.Tissue Bank DivisionUniversity of MiamiMiamiUSA

Personalised recommendations