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 ABCR  Vol.8 No.3 , July 2019
Serum Y-Box Binding Protein 1 (YBX-1) and Interleukin 6 (IL-6) Are Associated with Metastasis in Breast Cancer Patients
Abstract: Objectives: The aim of this study was to assess the levels of Y-box binding protein 1 (YBX-1) and interleukin 6 (IL-6) in the sera of metastatic and non-metastatic breast cancer patients (BC), investigate their clinicopathological significance and to analyze their potential use as biomarkers of breast cancer metastasis. Methods: The study included ninety subjects sub-grouped equally into metastatic BC, non-metastatic BC and healthy volunteers. Serum YBX-1 and IL-6 were quantified using ELISA technique while CA 15-3 was quantified using IRMA kit. Clinical data were collected from patients’ records. Results: YBX-1 (p < 0.001), IL-6 (p < 0.001) and CA15-3 (p = 0.017, 0.001) were significantly elevated in metastatic and non-metastatic BC patients compared to healthy controls, however, only YBX-1 (p < 0.001) and IL-6 (p < 0.001) showed a significant difference with cancer metastasis. Generally, YBX-1 and IL-6 were correlated with worse histological grade and late clinical stage in breast cancer patients and they were also associated with axillary lymph nodes involvement and positive vascular invasion in metastatic BC patients. Serum YBX-1 and IL-6 levels were positively correlated to each other (rs = 0.615, p < 0.001) and they showed high sensitivity and specificity compared to CA 15-3 (p < 0.001 and p = 0.004 for YBX-1 and IL-6 respectively) for predicting cancer metastasis. Conclusions: Serum YBX-1 and IL-6 are potential biomarkers of breast cancer patients with significant correlation with bad clinicopathological characteristics. Serum YBX-1 and IL-6 have superior sensitivity and specificity compared to CA15-3 and can serve as potential follow up and prognostic markers.
Cite this paper: K. Abd-Elaziz, C. , A. Abd El Moneim, N. , E. El Fek, S. and M. Arafat, A. (2019) Serum Y-Box Binding Protein 1 (YBX-1) and Interleukin 6 (IL-6) Are Associated with Metastasis in Breast Cancer Patients. Advances in Breast Cancer Research, 8, 119-134. doi: 10.4236/abcr.2019.83009.
References

[1]   Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R.L., Torre, L.A. and Jemal, A. (2018) Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. Cancer, 68, 394-424.
https://doi.org/10.3322/caac.21492

[2]   Lyabin, D.N., Eliseeva, I.A. and Ovchinnikov, L.P. (2014) YB-1 Protein: Functions and Regulation. Wiley Interdisciplinary Reviews: RNA, 5, 95-110.
https://doi.org/10.1002/wrna.1200

[3]   Zasedateleva, O.A., Krylov, A.S., Prokopenko, D.V., Skabkin, M.A., Ovchinnikov, L.P., Kolchinsky, A., et al. (2002) Specificity of Mammalian Y-Box Binding Protein p50 in Interaction with ss and ds DNA Analyzed with Generic Oligonucleotide Microchip. Journal of Molecular Biology, 324, 73-87.
https://doi.org/10.1016/S0022-2836(02)00937-3

[4]   Weydert, C., van Heertum, B., Dirix, L., De Houwer, S., De Wit, F., Mast, J., et al. (2018) Y-Box-Binding Protein 1 Supports the Early and Late Steps of HIV Replication. PLoS ONE, 13, e0200080.
https://doi.org/10.1371/journal.pone.0200080

[5]   Alemasova, E.E., Moor, N.A., Naumenko, K.N., Kutuzov, M.M., Sukhanova, M.V., Pestryakov, P.E., et al. (2016) Y-Box-Binding Protein 1 as a Non-Canonical Factor of Base Excision Repair. Biochimica et Biophysica Acta, 1864, 1631-1640.
https://doi.org/10.1016/j.bbapap.2016.08.012

[6]   Higashi, K., Inagaki, Y., Suzuki, N., Mitsui, S., Mauviel, A., Kaneko, H., et al. (2003) Y-Box-Binding Protein YB-1 Mediates Transcriptional Repression of Human Alpha 2(I) Collagen Gene Expression by Interferon-Gamma. The Journal of Biological Chemistry, 278, 5156-5162.
https://doi.org/10.1074/jbc.M208724200

[7]   Prabhu, L., Hartley, A.V., Martin, M., Warsame, F., Sun, E. and Lu, T. (2015) Role of Post-Translational Modification of the Y Box Binding Protein 1 in Human Cancers. Genes and Diseases, 2, 240-246.
https://doi.org/10.1016/j.gendis.2015.05.001

[8]   Lyabin, D.N., Doronin, A.N., Eliseeva, I.A., Guens, G.P., Kulakovskiy, I.V. and Ovchinnikov, L.P. (2014) Alternative Forms of Y-Box Binding Protein 1 and YB-1 mRNA. PLoS ONE, 9, e104513.
https://doi.org/10.1371/journal.pone.0104513

[9]   Nishio, S., Ushijima, K., Yamaguchi, T., Sasajima, Y., Tsuda, H., Kasamatsu, T., et al. (2014) Nuclear Y-Box-Binding Protein-1 Is a Poor Prognostic Marker and Related to Epidermal Growth Factor Receptor in Uterine Cervical Cancer. Gynecologic Oncology, 132, 703-708.
https://doi.org/10.1016/j.ygyno.2014.01.045

[10]   Panupinthu, N., Yu, S., Zhang, D., Zhang, F., Gagea, M., Lu, Y., et al. (2014) Self-Reinforcing Loop of Amphiregulin and Y-Box Binding Protein-1 Contributes to Poor Outcomes in Ovarian Cancer. Oncogene, 33, 2846-2856.
https://doi.org/10.1038/onc.2013.259

[11]   Guo, T., Yu, Y., Yip, G.W., Baeg, G.H., Thike, A.A., Lim, T.K., et al. (2015) Y-Box Binding Protein 1 Is Correlated with Lymph Node Metastasis in Intestinal-Type Gastric Cancer. Histopathology, 66, 491-499.
https://doi.org/10.1111/his.12570

[12]   Yan, X., Yan, L., Zhou, J., Liu, S., Shan, Z., Jiang, C., et al. (2014) High Expression of Y-Box-Binding Protein 1 Is Associated with Local Recurrence and Predicts Poor Outcome in Patients with Colorectal Cancer. International Journal of Clinical and Experimental Pathology, 7, 8715-8723.

[13]   Eliseeva, I.A., Kim, E.R., Guryanov, S.G., Ovchinnikov, L.P. and Lyabin, D.N. (2011) Y-Box-Binding Protein 1 (YB-1) and Its Functions. Biochemistry, 76, 1402-1433.
https://doi.org/10.1134/S0006297911130049

[14]   Nagasu, S., Sudo, T., Kinugasa, T., Yomoda, T., Fujiyoshi, K., Shigaki, T., et al. (2019) Y-Box-Binding Protein 1 Inhibits Apoptosis and Upregulates EGFR in Colon Cancer. Oncology Reports, 41, 2889-2896.
https://doi.org/10.3892/or.2019.7038

[15]   Yang, J.Y., Ha, S.A., Yang, Y.S. and Kim, J.W. (2010) p-Glycoprotein ABCB5 and YB-1 Expression Plays a Role in Increased Heterogeneity of Breast Cancer Cells: Correlations with Cell Fusion and Doxorubicin Resistance. BMC Cancer, 10, 388.
https://doi.org/10.1186/1471-2407-10-388

[16]   Evdokimova, V., Tognon, C., Ng, T., Ruzanov, P., Melnyk, N., Fink, D., et al. (2009) Translational Activation of Snail1 and Other Developmentally Regulated Transcription Factors by YB-1 Promotes an Epithelial-Mesenchymal Transition. Cancer Cell, 15, 402-415.
https://doi.org/10.1016/j.ccr.2009.03.017

[17]   Landskron, G., De La Fuente, M., Thuwajit, P., Thuwajit, C. and Hermoso, M.A. (2014) Chronic Inflammation and Cytokines in the Tumor Microenvironment. Journal of Immunology Research, 2014, Article ID: 149185.
https://doi.org/10.1155/2014/149185

[18]   Gyamfi, J., Eom, M., Koo, J.S. and Choi, J. (2017) Multifaceted Roles of Interleukin-6 in Adipocyte-Breast Cancer Cell Interaction. Translational Oncology, 11, 275-285.
https://doi.org/10.1016/j.tranon.2017.12.009

[19]   Zhang, S., Yang, X., Wang, L. and Zhang, C. (2018) Interplay between Inflammatory Tumor Microenvironment and Cancer Stem Cells. Oncology Letters, 16, 679-686.
https://doi.org/10.3892/ol.2018.8716

[20]   Sehgal, P.B. (2010) Interleukin-6 Induces Increased Motility, Cell-Cell and Cell-Substrate Dyshesion and Epithelial-to-Mesenchymal Transformation in Breast Cancer Cells. Oncogene, 29, 2599-2600.
https://doi.org/10.1038/onc.2010.4

[21]   Sullivan, N.J., Sasser, A.K., Axel, A.E., Vesuna, F., Raman, V., Ramirez, N., et al. (2009) Interleukin-6 Induces an Epithelial-Mesenchymal Transition Phenotype in Human Breast Cancer Cells. Oncogene, 28, 2940-2947.
https://doi.org/10.1038/onc.2009.180

[22]   Wang, X., Guo, X.B., Shen, X.C., Zhou, H., Wan, D.W., Xue, X.F., et al. (2015) Prognostic Role of YB-1 Expression in Breast Cancer: A Meta-Analysis. International Journal of Clinical and Experimental Medicine, 8, 1780.

[23]   Frye, B.C., Halfter, S., Djudjaj, S., Muehlenberg, P., Weber, S. and Raffetseder, U. (2009) Y-Box Protein-1 Is Actively Secreted through a Non-Classical Pathway and Acts as an Extracellular Mitogen. EMBO Reports, 10, 783-789.
https://doi.org/10.1038/embor.2009.81

[24]   Tacke, F., Galm, O., Kanig, N., Yagmur, E., Brandt, S., Lindquist, J.A., et al. (2014) High Prevalence of Y-Box Protein-1/p18 Fragment in Plasma of Patients with Malignancies of Different Origin. BMC Cancer, 14, 33.
https://doi.org/10.1186/1471-2407-14-33

[25]   Ma, Y., Ren, Y., Dai, Z.J., Wu, C.J., Ji, Y.H. and Xu, J. (2017) IL-6, IL-8 and TNF-Alpha Levels Correlate with Disease Stage in Breast Cancer Patients. Advances in Clinical and Experimental Medicine, 26, 421-426.
https://doi.org/10.17219/acem/62120

[26]   Milovanovic, J., Todorovic-Rakovic, N. and Radulovic, M. (2019) Interleukin-6 and Interleukin-8 Serum Levels in Prognosis of Hormone-Dependent Breast Cancer. Cytokine, 118, 93-98.
https://doi.org/10.1016/j.cyto.2018.02.019

[27]   Won, H.S., Kim, Y.A., Lee, J.S., Jeon, E.K., An, H.J., Sun, D.S., et al. (2013) Soluble Interleukin-6 Receptor Is a Prognostic Marker for Relapse-Free Survival in Estrogen Receptor-Positive Breast Cancer. Cancer Investigation, 8, 516-521.
https://doi.org/10.3109/07357907.2013.826239

[28]   Studebaker, A.W., Storci, G., Werbeck, J.L., Sansone, P., Sasser, A.K., Tavolari, S., et al. (2008) Fibroblasts Isolated from Common Sites of Breast Cancer Metastasis Enhance Cancer Cell Growth Rates and Invasiveness in an Interleukin-6-Dependent Manner. Cancer Research, 68, 9087-9095.
https://doi.org/10.1158/0008-5472.CAN-08-0400

[29]   Sasser, A.K., Sullivan, N.J., Studebaker, A.W., Hendey, L.F., Axel, A.E. and Hall, B.M. (2007) Interleukin-6 Is a Potent Growth Factor for ER-Alpha-Positive Human Breast Cancer. The FASEB Journal, 21, 3763-3770.
https://doi.org/10.1096/fj.07-8832com

[30]   Astanehe, A., Finkbeiner, M.R., Krzywinski, M., Fotovati, A., Dhillon, J., Berquin, I.M., et al. (2012) MKNK1 Is YB-1 Target Gene Responsible for Imparting Trastuzumab Resistance and Can Be Blocked by RSK Inhibition. Oncogene, 31, 4434-4446.
https://doi.org/10.1038/onc.2011.617

[31]   Castellana, B., Aasen, T., Moreno-Bueno, G., Dunn, S.E. and Ramón y Cajal, S. (2015) Interplay between YB-1 and IL-6 Promotes the Metastatic Phenotype in Breast Cancer Cells. Oncotarget, 6, 38239-38256.
https://doi.org/10.18632/oncotarget.5664

[32]   Grivennikov, S. and Karin, M. (2008) Autocrine IL-6 Signaling: A Key Event in Tumorigenesis? Cancer Cell, 13, 7-9.
https://doi.org/10.1016/j.ccr.2007.12.020

[33]   Song, Y.H., Shiota, M., Yokomizo, A., Uchiumi, T., Kiyoshima, K., Kuroiwa, K., et al. (2014) Twist1 and Y-Box-Binding Protein-1 Are Potential Prognostic Factors in Bladder Cancer. Urologic Oncology, 32, 31.e1-7.
https://doi.org/10.1016/j.urolonc.2012.11.003

[34]   Zhu, X., Tao, L., Yao, J., Sun, P., Pei, L., Li, J., et al. (2014) Identification of Collaboration Patterns of Dysfunctional Pathways in Breast Cancer. International Journal of Clinical and Experimental Pathology, 7, 3853-3864.

[35]   Ferreira, A.R., Bettencourt, M., Alho, I., Costa, A.L., Sousa, A.R. and Mansinho, A. (2017) Serum YB-1 (Y-Box Binding Protein 1) as a Biomarker of Bone Disease Progression in Patients with Breast Cancer and Bone Metastases. Journal of Bone Oncology, 6, 16-21.
https://doi.org/10.1016/j.jbo.2017.01.002

[36]   Huang, X., Ushijima, K., Komai, K., Takemoto, Y., Motoshima, S., Kamura, T. and Kohno, K. (2004) Co-Expression of Y Box-Binding Protein-1 and P-Glycoprotein as a Prognostic Marker for Survival in Epithelial Ovarian Cancer. Gynecologic Oncology, 93, 287-291.
https://doi.org/10.1016/j.ygyno.2004.01.040

[37]   Abd El-Maqsoud, N.M., Osman, N.A., Abd El-Hamid, A.M., Fath El-Bab, T.K. and Galal, E.M. (2016) Golgi Phosphoprotein-3 and Y-Box-Binding Protein-1 Are Novel Markers Correlating with Poor Prognosis in Prostate Cancer. Clinical Genitourinary Cancer, 14, e143-e152.
https://doi.org/10.1016/j.clgc.2015.12.015

[38]   Kariminia, A., Ivison, S.M., Leung, V.M., Sung, S., Couto, N., Rozmus, J., et al. (2017) Y-Box-Binding Protein 1 Contributes to IL-7-Mediated Survival Signaling in B-Cell Precursor Acute Lymphoblastic Leukemia. Oncology Letters, 13, 497-505.
https://doi.org/10.3892/ol.2016.5437

[39]   Chatterjee, M., Rancso, C., Stühmer, T., Eckstein, N., Andrulis, M., Gerecke, C., et al. (2008) The Y-Box Binding Protein YB-1 Is Associated with Progressive Disease and Mediates Survival and Drug Resistance in Multiple Myeloma. Blood, 111, 3714-3722.
https://doi.org/10.1182/blood-2007-05-089151

[40]   Rohr, I., Braicu, E.I., En-Nia, A., Heinrich, M., Richter, R., Chekerov, R., et al. (2016) Y-Box Protein-1/p18 as Novel Serum Marker for Ovarian Cancer Diagnosis: A Study by the Tumor Bank Ovarian Cancer (TOC). Cytokine, 85, 157-164.
https://doi.org/10.1016/j.cyto.2016.06.021

 
 
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