Abstract
Purpose
Y-box binding protein 1 (YB-1) expression in cancer cells is closely associated with malignant progression and poor prognosis in various cancers. Recently, we demonstrated that YB-1 expression in cancer cells is an immunomarker for patient prognosis and liver metastasis of gastric cancer (GC), and identified YB-1 as an excellent biomarker of angiogenic and proliferating endothelial cells in cancers. We further explored the expression patterns of YB-1 in gastric vasculature and the relationship with the clinical pathologic characteristics, as well as YB-1 phenotype in cancer cells.
Methods/Patients
Immunohistochemical analysis of YB-1 was performed using 163 surgically resected primary GC specimens.
Results
YB-1 expression in cancer cells significantly differed with respect to Lauren type, JGCA classification, vascular invasion (VI), and microvessel density (MVD) of cancers (P = 0.018, P = 0.002, P < 0.001, and P < 0.001, respectively). No correlation was found between cancer-cell YB-1 expression and TNM stage or lymphatic invasion. However, YB-1 expression in vascular endothelial cells significantly correlated with N stage, M stage, TNM stage, and MVD of cancers (P < 0.001, P = 0.013, P < 0.001, and P < 0.001, respectively). Notably, cases with YB-1 expression in cancer vasculature also demonstrated YB-1 expression in cancer cells (P = 0.040).
Conclusions
YB-1 may promote GC development through its function in both cancer cells and cancer vascular cells, and thus represent a potential biomarker in this disease.
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References
Ilson DH. Angiogenesis in gastric cancer: hitting the target? Lancet. 2013. doi:10.1016/S0140-6736(13)61892-9.
Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2013. doi:10.1016/S0140-6736(13)61719-5.
Razzak M. Targeted therapies: hope for antiangiogenic therapy in advanced gastric cancer. Nature rev Clin oncol. 2013;10(10):548. doi:10.1038/nrclinonc.2013.156.
Kohno K, Izumi H, Uchiumi T, Ashizuka M, Kuwano M. The pleiotropic functions of the Y-box-binding protein, YB-1. BioEssays. 2003;25(7):691–8. doi:10.1002/bies.10300.
Takahashi M, Shimajiri S, Izumi H, Hirano G, Kashiwagi E, Yasuniwa Y, et al. Y-box binding protein-1 is a novel molecular target for tumor vessels. Cancer Sci. 2010;101(6):1367–73. doi:10.1111/j.1349-7006.2010.01534.x.
Eliseeva IA, Kim ER, Guryanov SG, Ovchinnikov LP, Lyabin DN. Y-box-binding protein 1 (YB-1) and its functions. Biochemistry. 2011;76(13):1402–33. doi:10.1134/S0006297911130049.
Lasham A, Print CG, Woolley AG, Dunn SE, Braithwaite AW. YB-1: oncoprotein, prognostic marker and therapeutic target? Biochem J. 2013;449(1):11–23. doi:10.1042/BJ20121323.
Gluz O, Mengele K, Schmitt M, Kates R, Diallo-Danebrock R, Neff F, et al. Y-box-binding protein YB-1 identifies high-risk patients with primary breast cancer benefiting from rapidly cycled tandem high-dose adjuvant chemotherapy. J clin oncol. 2009;27(36):6144–51. doi:10.1200/JCO.2008.19.6261.
Wu Y, Yamada S, Izumi H, Li Z, Shimajiri S, Wang KY, et al. Strong YB-1 expression is associated with liver metastasis progression and predicts shorter disease-free survival in advanced gastric cancer. J Surg Oncol. 2012;105(7):724–30. doi:10.1002/jso.23030.
Faury D, Nantel A, Dunn SE, Guiot MC, Haque T, Hauser P, et al. Molecular profiling identifies prognostic subgroups of pediatric glioblastoma and shows increased YB-1 expression in tumors. J Clin Oncol. 2007;25(10):1196–208. doi:10.1200/JCO.2006.07.8626.
Oda Y, Ohishi Y, Saito T, Hinoshita E, Uchiumi T, Kinukawa N, et al. Nuclear expression of Y-box-binding protein-1 correlates with P-glycoprotein and topoisomerase II alpha expression, and with poor prognosis in synovial sarcoma. J Pathol. 2003;199(2):251–8. doi:10.1002/path.1282.
Shiota M, Izumi H, Onitsuka T, Miyamoto N, Kashiwagi E, Kidani A, et al. Twist promotes tumor cell growth through YB-1 expression. Cancer Res. 2008;68(1):98–105. doi:10.1158/0008-5472.CAN-07-2981.
Japanese Gastric Cancer A. Japanese classification of gastric carcinoma: 3rd English edition. Gastric cancer. 2011;14(2):101–12. doi:10.1007/s10120-011-0041-5.
Ohga T, Koike K, Ono M, Makino Y, Itagaki Y, Tanimoto M, et al. Role of the human Y box-binding protein YB-1 in cellular sensitivity to the DNA-damaging agents cisplatin, mitomycin C, and ultraviolet light. Cancer Res. 1996;56(18):4224–8.
Yasen M, Ka**o K, Kano S, Tobita H, Yamamoto J, Uchiumi T, et al. The up-regulation of Y-box binding proteins (DNA binding protein A and Y-box binding protein-1) as prognostic markers of hepatocellular carcinoma. Clin Cancer Res. 2005;11(20):7354–61. doi:10.1158/1078-0432.CCR-05-1027.
Hansen S, Grabau DA, Sorensen FB, Bak M, Vach W, Rose C. Vascular grading of angiogenesis: prognostic significance in breast cancer. Br J Cancer. 2000;82(2):339–47. doi:10.1054/bjoc.1999.0924.
Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, et al. Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst. 1992;84(24):1875–87.
Suzuki S, Dobashi Y, Hatakeyama Y, Tajiri R, Fujimura T, Heldin CH, et al. Clinicopathological significance of platelet-derived growth factor (PDGF)-B and vascular endothelial growth factor-A expression, PDGF receptor-beta phosphorylation, and microvessel density in gastric cancer. BMC Cancer. 2010;10:659. doi:10.1186/1471-2407-10-659.
Kitadai Y. Angiogenesis and lymphangiogenesis of gastric cancer. J oncol. 2010;2010:468725. doi:10.1155/2010/468725.
Shuman Moss LA, Jensen-Taubman S, Stetler-Stevenson WG. Matrix metalloproteinases: changing roles in tumor progression and metastasis. Am j pathol. 2012;181(6):1895–9. doi:10.1016/j.ajpath.2012.08.044.
Lykke-Andersen S, Brodersen DE, Jensen TH. Origins and activities of the eukaryotic exosome. J Cell Sci. 2009;122(Pt 10):1487–94. doi:10.1242/jcs.047399.
Grange C, Tapparo M, Collino F, Vitillo L, Damasco C, Deregibus MC, et al. Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res. 2011;71(15):5346–56. doi:10.1158/0008-5472.CAN-11-0241.
Moser JJ, Fritzler MJ. Cytoplasmic ribonucleoprotein (RNP) bodies and their relationship to GW/P bodies. Int j biochem cell biol. 2010;42(6):828–43. doi:10.1016/j.biocel.2009.11.018.
Furuya M, Yonemitsu Y. Cancer neovascularization and proinflammatory microenvironments. Curr Cancer Drug Target. 2008;8(4):253–65.
Hammerling GJ, Ganss R. Vascular integration of endothelial progenitors during multistep tumor progression. Cell Cycle. 2006;5(5):509–11.
Kosnopfel C, Sinnberg T, Schittek B. Y-box binding protein 1––A prognostic marker and target in tumour therapy. Eur J Cell Biol. 2013. doi:10.1016/j.ejcb.2013.11.007.
Nomura M, Yamagishi S, Harada S, Hayashi Y, Yamashima T, Yamashita J, et al. Possible participation of autocrine and paracrine vascular endothelial growth factors in hypoxia-induced proliferation of endothelial cells and pericytes. J Biol Chem. 1995;270(47):28316–24.
Li A, Varney ML, Valasek J, Godfrey M, Dave BJ, Singh RK. Autocrine role of interleukin-8 in induction of endothelial cell proliferation, survival, migration and MMP-2 production and angiogenesis. Angiogenesis. 2005;8(1):63–71. doi:10.1007/s10456-005-5208-4.
Vicari AP, Caux C. Chemokines in cancer. Cytokine Growth Factor Rev. 2002;13(2):143–54.
Lacal PM, Ruffini F, Pagani E, D’Atri S. An autocrine loop directed by the vascular endothelial growth factor promotes invasiveness of human melanoma cells. Int J Oncol. 2005;27(6):1625–32.
Tay WL, Yip GW, Tan PH, Matsumoto K, Yeo R, Ng TP, et al. Y-Box-binding protein-1 is a promising predictive marker of radioresistance and chemoradioresistance in nasopharyngeal cancer. Mod pathol. 2009;22(2):282–90. doi:10.1038/modpathol.2008.181.
Tsofack SP, Meunier L, Sanchez L, Madore J, Provencher D, Mes-Masson AM, et al. Low expression of the X-linked ribosomal protein S4 in human serous epithelial ovarian cancer is associated with a poor prognosis. BMC Cancer. 2013;13:303. doi:10.1186/1471-2407-13-303.
Song YH, Shiota M, Yokomizo A, Uchiumi T, Kiyoshima K, Kuroiwa K, et al. Twist1 and Y-box-binding protein-1 are potential prognostic factors in bladder cancer. Urol oncol. 2014;32(1):31.e1–7. doi:10.1016/j.urolonc.2012.11.003.
Shibata T, Kan H, Murakami Y, Ureshino H, Watari K, Kawahara A, et al. Y-box binding protein-1 contributes to both HER2/ErbB2 expression and lapatinib sensitivity in human gastric cancer cells. Mol Cancer Ther. 2013;12(5):737–46. doi:10.1158/1535-7163.MCT-12-1125.
Bargou RC, Jurchott K, Wagener C, Bergmann S, Metzner S, Bommert K, et al. Nuclear localization and increased levels of transcription factor YB-1 in primary human breast cancers are associated with intrinsic MDR1 gene expression. Nat Med. 1997;3(4):447–50.
Fujiwara-Okada Y, Matsumoto Y, Fukushi J, Setsu N, Matsuura S, Kamura S, et al. Y-box binding protein-1 regulates cell proliferation and is associated with clinical outcomes of osteosarcoma. Br J Cancer. 2013;108(4):836–47. doi:10.1038/bjc.2012.579.
Woolley AG, Algie M, Samuel W, Harfoot R, Wiles A, Hung NA, et al. Prognostic association of YB-1 expression in breast cancers: a matter of antibody. PLoS ONE. 2011;6(6):e20603. doi:10.1371/journal.pone.0020603.
Szczuraszek K, Halon A, Materna V, Mazur G, Wrobel T, Kuliczkowski K, et al. Elevated YB-1 expression is a new unfavorable prognostic factor in non-Hodgkin’s lymphomas. Anticancer Res. 2011;31(9):2963–70.
Acknowledgments
The authors thank Ms. H. Isagai for technical assistance. This study was supported in part by Grants-in-Aid for Scientific Research from the Ministry for Education, Culture, Sports, Science and Technology of Japan (No. 24501323), a University of Occupational and Environmental Health Grant for Advanced Research, and the Vehicle Racing Commemorative Foundation, and a grant from the National Natural Science Foundation of China (No. 81201801).
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Supplemental Fig. Western blot for the exosome-related proteins HLA-A (Santa Cruz, USA; 1:500) and TSG101 (Santa Cruz, USA; 1:500) and YB-1 (1:5000) in cell lysis and exosomes derived from gastric cancer cell line SGC-7901. YB-1 is positive in the cancer-derived exosomes.
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Wu, Y., Wang, KY., Li, Z. et al. Y-box binding protein 1 expression in gastric cancer subtypes and association with cancer neovasculature. Clin Transl Oncol 17, 152–159 (2015). https://doi.org/10.1007/s12094-014-1208-4
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DOI: https://doi.org/10.1007/s12094-014-1208-4