Advertisement

Tumor Biology

, Volume 37, Issue 8, pp 10577–10586 | Cite as

Differential expression of PDGFRB and EGFR in microvascular proliferation in glioblastoma

  • Guiyan Xu
  • Jian Yi Li
Original Article

Abstract

Glioblastoma (GBM) is the highly malignant glioma and exhibits microvascular proliferation. PCR mRNA arrays and immunohistochemical stains on tissue microarray demonstrated that the expression level of PDGFRB in GBM microvascular proliferation was significantly higher than that in GBM tumor cells while the expression level of EGFR was lower in microvascular proliferation than in GBM tumor cells. PDGFRB protein was selectively expressed in pericytes in GBM microvascular proliferation. By analyzing The Cancer Genome Atlas (TCGA) datasets for GBM, it was found that genomic DNA alterations were the main reason for the high expression of EGFR in GBM tumor cells. Our miRNA microarray data showed that microRNAs (miRNAs) (miR-193b-3p, miR-518b, miR-520f-3p, and miR-506-5p) targeting PDGFRB were downregulated in microvascular proliferation, which might be the most likely reason for the high expression of PDGFRB in GBM microvascular proliferation. The increase of several miRNAs (miR-133b, miR-30b-3p, miR-145-5p, and miR-146a-5p) targeting EGFR in GBM microvascular proliferation was one of the reasons for the lack of expression of EGFR in GBM microvascular proliferation. These findings implicated that miRNAs, such as miR-506, miR-133b, miR-145, and miR-146a, that target PDGFRB or EGFR, might be potential therapeutic agents for GBM. A new generation of targeted therapeutic agents against both EGFR and PDGFRB might be developed in the future.

Keyword

Glioblastoma Microvascular proliferation PDGFRB EGFR PCR array Tissue microarray MicroRNA (miRNA) 

Notes

Acknowledgments

We give special thanks to Dr. Betty Diamond, who provided the lab space and equipments. We also appreciate help and support from all her lab members. We are thankful for Mr. Daniel Loen and Ms. Jill Wishinsky for managing the Grant. Dept. of Pathology and Lab. Medicine: We thank Dr. James Crawford for his support and encouragement, Ms. Claudine Alexis for ordering all our materials, and people in histology laboratory and immunostain laboratory for technical support.

Compliance with ethical standards

This study was approved by the North Shore and Long Island Jewish Health System Institutional Review Board.

Funding

This work was supported by North Shore-LIJ Cancer Institute.

Conflicts of interest

None

References

  1. 1.
    Kleihues P, Burger P, Aldape K, et al. Glioblastoma. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO classification of tumours of the central nervous system. Lyon: IARC Press; 2007. p. 33–49.Google Scholar
  2. 2.
    Norden AD, Young GS, Setayesh K, et al. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence 1. Neurology. 2008;70:779–87.CrossRefPubMedGoogle Scholar
  3. 3.
    Wesseling P, Claes A, Maass C. Combined temozolomide (TMZ) and anti-angiogenic therapy of gliomas: a capricious cocktail? Neuro-Oncology. 2007. Ref Type: Conference Proceeding.Google Scholar
  4. 4.
    Xu G, Li JY. ATP5A1 and ATP5B are highly expressed in glioblastoma tumor cells and endothelial cells of microvascular proliferation. J Neuro-Oncol. 2016;126:405–13.Google Scholar
  5. 5.
    Kononen J, Bubendorf L, Kallioniemi A, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998;4:844–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.CrossRefPubMedGoogle Scholar
  7. 7.
    Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:l1.CrossRefGoogle Scholar
  8. 8.
    Hsu SD, Tseng YT, Shrestha S, et al. miRTarBase update 2014: an information resource for experimentally validated miRNA-target interactions. Nucleic Acids Res. 2014;42:D78–85.CrossRefPubMedGoogle Scholar
  9. 9.
    Chan AS, Leung SY, Wong MP, et al. Expression of vascular endothelial growth factor and its receptors in the anaplastic progression of astrocytoma, oligodendroglioma, and ependymoma. Am J Surg Pathol. 1998;22:816–26.CrossRefPubMedGoogle Scholar
  10. 10.
    Grau SJ, Trillsch F, Herms J, et al. Expression of VEGFR3 in glioma endothelium correlates with tumor grade. J Neuro-Oncol. 2007;82:141–50.CrossRefGoogle Scholar
  11. 11.
    Crespo I, Vital AL, Gonzalez-Tablas M, et al. Molecular and genomic alterations in glioblastoma multiforme. Am J Pathol. 2015;185:1820–33.CrossRefPubMedGoogle Scholar
  12. 12.
    Heimberger AB, Suki D, Yang D, Shi W, Aldape K. The natural history of EGFR and EGFRvIII in glioblastoma patients. J Transl Med. 2005;3:38.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Nazarenko I, Hede SM, He X, et al. PDGF and PDGF receptors in glioma. Ups J Med Sci. 2012;117:99–112.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ahmed FE. Role of miRNA in carcinogenesis and biomarker selection: a methodological view. Expert Rev Mol Diagn. 2007;7:569–603.CrossRefPubMedGoogle Scholar
  15. 15.
    Liu Z, Liu Y, Li L, et al. MiR-7-5p is frequently downregulated in glioblastoma microvasculature and inhibits vascular endothelial cell proliferation by targeting RAF1. Tumour Biol. 2014;35:10177–84.CrossRefPubMedGoogle Scholar
  16. 16.
    Zhong Q, Wang T, Lu P, Zhang R, Zou J, Yuan S. miR-193b promotes cell proliferation by targeting Smad3 in human glioma. J Neurosci Res. 2014;92:619–26.CrossRefPubMedGoogle Scholar
  17. 17.
    Li Z, Liu Z, Dong S, et al. miR-506 inhibits epithelial-to-mesenchymal transition and angiogenesis in gastric cancer. Am J Pathol. 2015;185:2412–20.CrossRefPubMedGoogle Scholar
  18. 18.
    Sun Y, Hu L, Zheng H, et al. MiR-506 inhibits multiple targets in the epithelial-to-mesenchymal transition network and is associated with good prognosis in epithelial ovarian cancer. J Pathol. 2015;235:25–36.CrossRefPubMedGoogle Scholar
  19. 19.
    Arora H, Qureshi R, Park WY. miR-506 regulates epithelial mesenchymal transition in breast cancer cell lines. PLoS One. 2013;8, e64273.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Liu G, Sun Y, Ji P, et al. MiR-506 suppresses proliferation and induces senescence by directly targeting the CDK4/6-FOXM1 axis in ovarian cancer. J Pathol. 2014;233:308–18.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Wang Y, Cui M, Sun BD, Liu FB, Zhang XD, Ye LH. MiR-506 suppresses proliferation of hepatoma cells through targeting YAP mRNA 3'UTR. Acta Pharmacol Sin. 2014;35:1207–14.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Yang FQ, Zhang HM, Chen SJ, Yan Y, Zheng JH. Correction: MiR-506 is down-regulated in clear cell renal cell carcinoma and inhibits cell growth and metastasis via targeting FLOT1. PLoS One. 2015;10, e0129404.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Yu F, Lv M, Li D, et al. MiR-506 over-expression inhibits proliferation and metastasis of breast cancer cells. Med Sci Monit. 2015;21:1687–92.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Wang J, Li Y, Jiang C. MiR-133b contributes to arsenic-induced apoptosis in U251 glioma cells by targeting the hERG channel. J Mol Neurosci. 2015;55:985–94.CrossRefPubMedGoogle Scholar
  25. 25.
    Zhou J, Lv L, Lin C, et al. Combinational treatment with microRNA133b and cetuximab has increased inhibitory effects on the growth and invasion of colorectal cancer cells by regulating EGFR. Mol Med Rep. 2015.Google Scholar
  26. 26.
    Lee HK, Bier A, Cazacu S, et al. MicroRNA-145 is downregulated in glial tumors and regulates glioma cell migration by targeting connective tissue growth factor. PLoS One. 2013;8, e54652.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Shi L, Wang Z, Sun G, Wan Y, Guo J, Fu X. miR-145 inhibits migration and invasion of glioma stem cells by targeting ABCG2. Neruomol Med. 2014;16:517–28.CrossRefGoogle Scholar
  28. 28.
    Lu Y, Chopp M, Zheng X, Katakowski M, Buller B, Jiang F. MiR-145 reduces ADAM17 expression and inhibits in vitro migration and invasion of glioma cells. Oncol Rep. 2013;29:67–72.PubMedGoogle Scholar
  29. 29.
    Rani SB, Rathod SS, Karthik S, Kaur N, Muzumdar D, Shiras AS. MiR-145 functions as a tumor-suppressive RNA by targeting Sox9 and adducin 3 in human glioma cells. Neuro-Oncology. 2013;15:1302–16.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Cho WC, Chow AS, Au JS. MiR-145 inhibits cell proliferation of human lung adenocarcinoma by targeting EGFR and NUDT1. RNA Biol. 2011;8:125–31.CrossRefPubMedGoogle Scholar
  31. 31.
    Xu B, Wang N, Wang X, et al. MiR-146a suppresses tumor growth and progression by targeting EGFR pathway and in a p-ERK-dependent manner in castration-resistant prostate cancer. Prostate. 2012;72:1171–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Ali S, Ahmad A, Aboukameel A, et al. Deregulation of miR-146a expression in a mouse model of pancreatic cancer affecting EGFR signaling. Cancer Lett. 2014;351:134–42.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    van den Bent MJ, Brandes AA, Rampling R, et al. Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol. 2009;27:1268–74.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineNorth Shore University Hospital and Long Island Jewish Medical Center, Hofstra Northwell School of Medicine, Northwell HealthLake SuccessUSA
  2. 2.Cancer Institute, Northwell HealthLake SuccessUSA

Personalised recommendations