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IGF-binding protein 2 is a candidate target of therapeutic potential in cancer

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Tumor Biology

Abstract

Insulin-like growth factor (IGF)-binding protein 2(IGFBP2), a key member of IGF family, has been reported as a notable oncogene in most human epithelium cancers. Increasing evidences suggested that IGFBP2 might be a candidate target of therapuetic potential by regulating key cancer metastasis and invasion-associated signaling networks, but there is still confusion about the mechanism on how IGFBP2 takes part in these processes. In this review, we summarized the current points of view that IGFBP2 functions in signaling pathways during tumorigenesis and tumor progression and discussed its potential clinical applications as a therapeutic target.

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References

  1. Cao Y et al. Prediagnostic plasma IGFBP-1, IGF-1 and risk of prostate cancer. Int J Cancer. 2015;136(10):2418–26.

    Article  CAS  PubMed  Google Scholar 

  2. Pollak M. Insulin and insulin-like growth factor signaling in neoplasia. Nat Rev Cancer. 2008;8(12):915–28.

    Article  CAS  PubMed  Google Scholar 

  3. Šunderić M et al. Molecular forms of the insulin-like growth factor-binding protein-2 in patients with colorectal cancer. Exp Mol Pathol. 2014;96(1):48–53.

    Article  PubMed  Google Scholar 

  4. Ahani N et al. Expression of insulin-like growth factor binding protein-2 (IGFBP-2) gene in negative and positive human cytomegalovirus glioblastoma multiforme tissues. Med Oncol. 2014;31(2):812.

    Article  PubMed  Google Scholar 

  5. Kricker JA et al. Structural and functional evidence for the interaction of insulin-like growth factors (IGFs) and IGF binding proteins with vitronectin. Endocrinology. 2003;144(7):2807–15.

    Article  CAS  PubMed  Google Scholar 

  6. Fukushima T, Kataoka H. Roles of insulin-like growth factor binding protein-2 (IGFBP-2) in glioblastoma. Anticancer Res. 2007;27(6A):3685–92.

    CAS  PubMed  Google Scholar 

  7. Rohrmann S et al. Concentrations of IGF-I and IGFBP-3 and pancreatic cancer risk in the European prospective investigation into cancer and nutrition. Br J Cancer. 2012;106(5):1004–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rowlands MA et al. Serum insulin-like growth factors and mortality in localized and advanced clinically detected prostate cancer. Cancer Causes Control. 2012;23(2):347–54.

    Article  PubMed  Google Scholar 

  9. Liou JM et al. Plasma insulin-like growth factor-binding protein-2 levels as diagnostic and pognostic biomarker of colorectal cancer. J Clin Endocrinol Metab. 2010;95(4):1717–25.

    Article  CAS  PubMed  Google Scholar 

  10. Ma J et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-1 and IGF-binding protein-3. J Natl Cancer Inst. 1999;91(7):620–5.

    Article  CAS  PubMed  Google Scholar 

  11. Miyake H et al. Introduction of insulin-like growth factor binding protein-2 gene into human bladder cancer cells enhances their metastatic potential. Oncol Rep. 2005;13(2):341–5.

    CAS  PubMed  Google Scholar 

  12. Wang H et al. Insulin-like growth factor binding protein2 enhances glioblastoma invasion by activating invasion-enhancing genes. Cancer Res. 2003;63(15):4315–21.

    CAS  PubMed  Google Scholar 

  13. Carrick FE et al. BIAcore analysis of bovine insulin-like growth factor (IGF)-binding protein-2 identifies major IGF binding site determinants in both the amino- and carboxyl-terminal domains. J Biol Chem. 2001;276(29):27120–8.

    Article  CAS  PubMed  Google Scholar 

  14. Headey SJ et al. Contributions of the N- and C-terminal domains of IGF binding protein-6 to IGF binding. J Mol Endocrinol. 2004;33(2):377–86.

    Article  CAS  PubMed  Google Scholar 

  15. Zesławski W et al. The interaction of insulin-like growth factor-1 with the N-terminal domain of IGFBP-5. EMBO J. 2001;20(14):3638–44.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Galea CA et al. Insulin-like growth factor binding protein-2: NMR analysis and structural characterization of the N-terminal domain. Biochimie. 2012;94(3):608–16.

    Article  CAS  PubMed  Google Scholar 

  17. Sitar T et al. Structural basis for the inhibition of insulin-like growth factors by insulin-like growth factor-binding proteins. Proc Natl Acad Sci U S A. 2006;103(35):13028–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Swain M et al. High-yield bacterial expression and structural characterization of recombinant human insulin-like growth factor binding protein-2. Arch Biochem Biophys. 2010;501(2):195–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Holmes KM et al. Insulin-like growth factor-binding protein 2-driven glioma progression isprevented by blocking a clinically significant integrin, integrin-linked kinase, and NF-kB network. Proc Natl Acad Sci U S A. 2012;109(9):3475–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wheatcroft SB et al. IGF-dependent and IGF-independent actions of IGF-binding protein-1 and −2: implications for metabolic homeostasis. Trends Endocrinol Metab. 2009;20(4):153–62.

    Article  CAS  PubMed  Google Scholar 

  21. Kawai M et al. The heparin-binding domain of IGFBP-2 has insulin-like growth factor binding-independent biologic activity in the growing skeleton. J Biol Chem. 2011;286(16):14670–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mehrian-Shai R et al. Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer. Proc Natl Acad Sci U S A. 2007;104(13):5563–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dunlap SM et al. Insulin-like growth factor binding protein 2 promotes glioma development and progression. Proc Natl Acad Sci U S A. 2007;104(28):11736–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Han S et al. Exogenous IGFBP-2 promotes proliferation, invasion, and chemoresistance to temozolomide in glioma cells via the integrin β1-ERK pathway. Br J Cancer. 2014;111(7):1400–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Moore LM et al. IGFBP2 is a candidate biomarker for Ink4a-Arf status and a therapeutic target for high-grade gliomas. Proc Natl Acad Sci U S A. 2009;106(39):16675–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Song SW et al. IIp45, an insulin-like growth factor binding protein 2 (IGFBP-2) binding protein, antagonizes IGFBP-2 stimulation of glioma cell invasion. Proc Natl Acad Sci U S A. 2003;100(24):13970–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Biernacka KM et al. Hyperglycaemia-induced chemoresistance of prostate cancer cells due to IGFBP2. Endocr Relat Cancer. 2013;20(5):741–51.

    Article  CAS  PubMed  Google Scholar 

  28. Uzoh CC et al. Insulin-like growth factor-binding protein-2 promotes prostate cancer cell growth via IGF-dependent or -independent mechanisms and reduces the efficacy of docetaxel. Br J Cancer. 2011;104(10):1587–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Neuhouser ML et al. Insulin-like growth factors and insulin-like growth factor-binding proteins and prostate cancer risk: results from the prostate cancer prevention trial. Cancer Prev Res. 2013;6(7):91–9.

    Article  CAS  Google Scholar 

  30. Dean SJ et al. Loss of PTEN expression is associated with IGFBP2 expression, younger age, and late stage in triple-negativebreast cancer. Am J Clin Pathol. 2014;141(3):323–33.

    Article  PubMed  Google Scholar 

  31. So AI et al. Insulin-like growth factor binding protein-2 is a novel therapeutic target associated with breast cancer. Clin Cancer Res. 2008;14(21):6944–54.

    Article  CAS  PubMed  Google Scholar 

  32. Migita T et al. Role of insulin-like growth factor binding protein 2 in lung adenocarcinoma: IGF-independent antiapoptotic effect via caspase-3. Am J Pathol. 2010;176(4):1756–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang Y et al. Autoantibodies against insulin-like growth factor protein-2 as a serological biomarker in the diagnosis of lung cancer. Int J Oncol. 2013;42(1):93–100.

    PubMed  Google Scholar 

  34. Kühnl A et al. High expression of IGFBP2 is associated with chemoresistance in adult acute myeloid leukemia. Leuk Res. 2011;35(12):1585–90.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Dawczynski K et al. Elevated serum insulin-like growth factor binding protein-2 is associated with a high relapse risk after hematopoietic stem cell transplantation in childhood AML. Bone Marrow Transplant. 2006;37(6):589–94.

    Article  CAS  PubMed  Google Scholar 

  36. Renehan AG et al. Elevated serum insulin-like growth factor (IGF)-II and IGF binding protein-2 in patients with colorectal cancer. Br J Cancer. 2000;83(10):1344–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Huang YF et al. Circulating IGF system and treatment outcome in epithelial ovarian cancer. Endocr Relat Cancer. 2014;21(2):217–29.

    Article  CAS  PubMed  Google Scholar 

  38. Zhang L et al. Expression of IGFBP2 in gastric carcinoma and relationship with clinicpathologic parameters and cell proliferation. Dig Dis Sci. 2007;52(1):248–53.

    Article  PubMed  Google Scholar 

  39. Tombolan L et al. High IGFBP2 expression correlates with tumor severity in pediatric rhabdomyosarcoma. Am J Pathol. 2011;179(5):2611–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang H et al. Expression of insulin-like growth factorbinding protein 2 in melanocytic lesions. J Cutan Pathol. 2003;30(10):599–605.

    Article  PubMed  Google Scholar 

  41. Wang GK et al. An interaction between insulin-like growth factor-binding protein 2 (IGFBP2) and integrin alpha5 is essential for IGFBP2-induced cell mobility. J Biol Chem. 2006;281(20):14085–91.

    Article  CAS  PubMed  Google Scholar 

  42. Mendes KN et al. JNK mediates insulin-like growth factor binding protein2/integrin alpha5-dependent glioma cell migration. Int J Oncol. 2010;37(1):143–53.

    CAS  PubMed  Google Scholar 

  43. Hsieh D et al. IGFBP2 promotes glioma tumor stem cell expansion and survival. Biochem Biophys Res Commun. 2010;397(2):367–72.

    Article  CAS  PubMed  Google Scholar 

  44. Foulstone EJ et al. Insulin-like growth factor binding protein 2 (IGFBP-2) promotes growth and survival of breast epithelial cells: novel regulation of the estrogen receptor. Endocrinology. 2013;154(5):1780–93.

    Article  CAS  PubMed  Google Scholar 

  45. Lu H et al. IGFBP2/FAK pathway is causally associated with dasatinib resistance in non-small cell lung cancer cells. Mol Cancer Ther. 2013;12(12):2864–73.

    Article  CAS  PubMed  Google Scholar 

  46. Chen X et al. IGF binding protein 2 is a cell-autonomous factor supporting survival and migration of acute leukemia cells. J Hematol Oncol. 2013;6(1):72.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Ben-Shmuel A et al. Global analysis of L1-transcriptomes identified IGFBP-2 as a target of ezrin and NF-κB signaling that promotes colon cancer progression. Oncogene. 2013;32(27):3220–30.

    Article  CAS  PubMed  Google Scholar 

  48. Chakrabarty S, Kondratick L. Insulin-like growth factor binding protein-2 stimulates proliferation and activates multiple cascades of the mitogen-activated protein kinase pathways in NIH-OVCAR3 human epithelial ovarian cancer cells. Cancer Biol Ther. 2006;5(2):189–97.

    Article  CAS  PubMed  Google Scholar 

  49. Lancaster JM et al. High expression of insulin-like growth factor binding protein–2 messenger RNA in epithelial ovarian cancers produces elevated preoperative serum levels. Int J Gynecol Cancer. 2006;16(4):1529–35.

    Article  CAS  PubMed  Google Scholar 

  50. Kang Z et al. Downregulation of IGFBP2 is associated with resistance to IGF1R therapy in rhabdomyosarcoma. Oncogene. 2014;33(50):5697–705.

    Article  CAS  PubMed  Google Scholar 

  51. Das SK et al. MDA-9/Syntenin and IGFBP-2 promote angiogenesis in human melanoma. Cancer Res. 2013;73(2):844–54.

    Article  CAS  PubMed  Google Scholar 

  52. Wang HM et al. IGFBP2 and IGFBP5 overexpression correlates with the lymph node metastasis in T1 breast carcinomas. Breast J. 2008;14(3):261–7.

    Article  PubMed  Google Scholar 

  53. Wieczorek E et al. Matrix metalloproteinases and genetic mouse models in cancer research: a mini-review. Tumour Biol. 2015;36(1):163–75.

    Article  CAS  PubMed  Google Scholar 

  54. Verma S et al. Matrix metalloproteinases and gastrointestinal cancers: impacts of dietary antioxidants. World J Biol Chem. 2014;5(3):355–76.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Azar WJ et al. IGFBP-2 enhances VEGF gene promoter activity and consequent promotion of angiogenesis by neuroblastoma cells. Endocrinology. 152(9):3332–42.

  56. Zhu Z et al. Inhibition of PKR impairs angiogenesis through VEGF pathway. Am J Physiol Endocrinol Metab. 2015;308(6):E518–24.

    Article  CAS  PubMed  Google Scholar 

  57. Godard S et al. Classification of human astrocytic gliomas on the basis of gene expression: a correlated group of genes with angiogenic activity emerges as a strong predictor of subtypes. Cancer Res. 2003;63(20):6613–25.

    CAS  PubMed  Google Scholar 

  58. Jing T et al. CD146 is a coreceptor for VEGFR-2 in tumor angiogenesis. Blood. 2012;120(11):2330–9.

    Article  Google Scholar 

  59. Firth SM, Baxter RC. Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev. 2002;23(6):824–54.

    Article  CAS  PubMed  Google Scholar 

  60. Conover CA. Isulin-like growth factor-binding proteins and bone metabolism. Am J Physiol Endocrinol Metab. 2008;294(1):E10–4.

    Article  CAS  PubMed  Google Scholar 

  61. Shen X et al. Insulin-like growth factor (IGF) binding protein 2 functions coordinately with receptor protein tyrosine phosphatase β and the IGF-I receptor to regulate IGF-I-stimulated signaling. Mol Cell Biol. 2012;32(20):4116–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Russo VC et al. Insulin-like growth factor binding protein-2 binding to extracellular matrix plays a critical role in neuroblastoma cell proliferation, migration, and invasion. Endocrinology. 2005;146(10):4445–55.

    Article  CAS  PubMed  Google Scholar 

  63. Lund J et al. Heparin-binding mechanism of the IGF2/IGF-binding protein 2 complex. J Mol Endocrinol. 2014;52(3):345–55.

    Article  CAS  PubMed  Google Scholar 

  64. Diehl D et al. IGFBP-2 overexpression reduces the appearance of dysplastic aberrant crypt foci and inhibits growth of adenomas in chemically induced colorectal carcinogenesis. Int J Cancer. 2009;124(9):2220–5.

    Article  CAS  PubMed  Google Scholar 

  65. Hang XP et al. Genetic variations in the IGF-IGFR-IGFBP axis confer susceptibility to lung and esophageal cancer. Genet Mol Res. 2014;13(1):2107–19.

    Google Scholar 

  66. Png KJ et al. A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells. Nature. 2011;481(7380):190–4.

    Article  PubMed  Google Scholar 

  67. Scagliotti GV, Novello S. The role of the insulin-like growth factor signaling pathway in non-small cell lung cancer and other solid tumors. Cancer Treat Rev. 2012;38(4):292–302.

    Article  CAS  PubMed  Google Scholar 

  68. Zhang CC et al. Angiopoietin-like 5 and IGFBP2 stimulate ex vivo expansion of human cord blood hematopoietic stem cells as assayed by NOD/SCID transplantation. Blood. 2008;111(7):3415–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Becher OJ et al. IGFBP2 is overexpressed by pediatric malignant astrocytomas and induces the repair enzyme DNA-PK. J Child Neurol. 2008;23(10):1205–13.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Grimberg A et al. Insulin-like growth factor factor binding protein-2 is a novel mediator of p53 inhibition of insulin-like growth factor signaling. Cancer Biol Ther. 2006;5(10):1408–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Fukushima T et al. Silencing of insulin-like growth factor-binding protein-2 in human glioblastoma cells reduces both invasiveness and expression of progression-associated gene CD24. J Biol Chem. 2007;282(25):18634–44.

    Article  CAS  PubMed  Google Scholar 

  72. Sun C et al. PTEN regulation of the proliferation and differentiation of auditory progenitors through the PTEN/PI3K/Akt-signaling pathway in mice. Neuroreport. 2014;25(3):177–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Carnero A, Paramio JM. The PTEN/PI3K/AKT pathway in vivo, cancer mouse models. Front Oncol. 2014;23(4):252.

    Google Scholar 

  74. Mireuta M et al. IGFBP-2 expression in MCF-7 cells is regulated by the PI3K/AKT/mTOR pathway through Sp1-induced increase in transcription. Growth Factors. 2010;28(4):243–55.

    Article  CAS  PubMed  Google Scholar 

  75. Sheldrake HM, Patterson LH. Strategies to inhibit tumor associated integrin receptors: rationale for dual and multi-antagonists. J Med Chem. 2014;57(15):6301–15.

    Article  CAS  PubMed  Google Scholar 

  76. Sun CC et al. Integrins: players in cancer progression and targets in cancer therapy. Anticancer Drugs. 2014;25(10):1107–21.

    Article  CAS  PubMed  Google Scholar 

  77. Schütt BS et al. Integrin-mediated action of insulin-like growth factor binding protein-2 in tumor cells. J Mol Endocrinol. 2004;32(3):859–68.

    Article  PubMed  Google Scholar 

  78. Wani AA et al. Integrin-linked kinase regulates melanoma angiogenesis by activating NF-kB /interleukin-6 signaling pathway. Oncogene. 2011;30(24):2778–88.

    Article  CAS  PubMed  Google Scholar 

  79. Yang M et al. The role of integrin-β/FAK in cyclic mechanical stimulation in MG-63 cells. Int J Clin Exp Pathol. 2014;7(11):7451–9.

    PubMed  PubMed Central  Google Scholar 

  80. Cox BD et al. New concepts regarding focal adhesion kinase promotion of cell migration and proliferation. J Cell Biochem. 2006;99(1):35–52.

    Article  PubMed  Google Scholar 

  81. Monasor A et al. INK4a/ARF limits the expansion of cells suffering from replication stress. Cell Cycle. 2013;12(12):1948–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Tang MR et al. CD24 expression predicts poor prognosis for patients with cutaneous malignant melanoma. Int J Clin Exp Med. 2014;7(11):4337–41.

    PubMed  PubMed Central  Google Scholar 

  83. Wu JX et al. Clinicopathological and prognostic significance of CD24 overexpression in patients with gastric cancer: a meta-analysis. PLoS One. 2014;9(12):E114746.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Villani RM et al. Patched1 inhibits epidermal progenitor cell expansion and basal cell carcinoma formation by limiting igfbp2 activity. Cancer Prev Res. 2010;3(10):1222–34.

    Article  CAS  Google Scholar 

  85. Sineva GS, Pospelov VA. β-Catenin in pluripotency: adhering to self-renewal or wnting to differentiate. Int Rev Cell Mol Biol. 2014;312:53–78.

    Article  CAS  PubMed  Google Scholar 

  86. Sehgal P et al. Regulation of protumorigenic pathways by insulin like growth factor binding protein2 and its association along with β-catenin in breast cancer lymph node metastasis. Mol Cancer. 2013;12:63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Miyako K et al. PAPA-1 is a nuclear binding partner of IGFBP-2 and modulates its growth-promoting actions. Mol Endocrinol. 2009;23(2):169–75.

    Article  CAS  PubMed  Google Scholar 

  88. Brana I et al. A parallel-arm phase I trial of the humanized anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours. Br J Cancer. 2014;111(10):1932–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Willky BA et al. A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours. Br J Cancer. 2015;112(1):24–31.

    Article  Google Scholar 

  90. Halvorson KG et al. A high-throughput in vitro drug screen in a genetically engineered mouse model of diffuse intrinsic pontine glioma identifies BMS-754807 as a promising therapeutic agent. PLoS One. 2015;10(3):E0118926.

    Article  PubMed  PubMed Central  Google Scholar 

  91. McCaffery I et al. Putative predictive biomarkers of survival in patients with metastatic pancreatic adenocarcinoma treated with gemcitabine and ganitumab, an IGF1R inhibitor. Clin Cancer Res. 2013;19(15):4282–9.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by a grant from the national Natural Science Foundation of China (81172573).

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Authors and Affiliations

  1. Department of Maxillofacial and Otorhinolaryngology Head & Neck Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People’s Republic of China

    Xiaofeng Yao, Shanshan Sun, Xuan Zhou, Wenyu Guo & Lun Zhang

  2. National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People’s Republic of China

    Xiaofeng Yao, Shanshan Sun, Xuan Zhou, Wenyu Guo & Lun Zhang

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  1. Xiaofeng Yao
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  2. Shanshan Sun
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  5. Lun Zhang
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Correspondence to Lun Zhang.

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Yao, X., Sun, S., Zhou, X. et al. IGF-binding protein 2 is a candidate target of therapeutic potential in cancer. Tumor Biol. 37, 1451–1459 (2016). https://doi.org/10.1007/s13277-015-4561-1

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