Sphk1 Expression and Survival Outcomes in Squamous Cell Carcinoma of the Oral Cavity


Sphingosine kinase 1 (SphK1) is an important mediator of apoptosis and the proliferation of cancer cells. It is upregulated in cells showing increasing radioresistance. Here we present the correlation between SphK1 expression and survival outcomes in patients with carcinoma of the oral cavity. A retrospective chart review was performed between January 2009 and August 2010 at the University of Southern California. Patients diagnosed with an advanced-stage primary tumor restricted to the oral cavity and a minimum follow-up of two years were included. Patients who did not receive post-operative radiation therapy were excluded. Eighteen patients met the inclusion criteria with 10 (55.6%) patients demonstrating high expression of SphK1 and 8 (44.4%) patients demonstrating a low-to-moderate expression of SphK1. Tumor recurrence occurred in 9 patients (50.0%): 5 patients (27.8%) in the SphK1high cohort at a mean time to progression of 2.5 mo and 4 patients (22.2%) in the SphK1low cohort at a mean time to progression of 11.0 mo (p = 0.023). Death occurred in 8 patients (66.7%) in the SphK1high cohort and 3 patients (16.7%) in the SphK1low cohort (p = 0.036). Higher expression of SphK1 correlates with greater radioresistance and poorer survival outcomes in patients with HNSCC of the oral cavity.

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B. Harris, R. Masood and U. Sinha, "Sphk1 Expression and Survival Outcomes in Squamous Cell Carcinoma of the Oral Cavity," Journal of Cancer Therapy, Vol. 4 No. 3, 2013, pp. 704-708. doi: 10.4236/jct.2013.43086.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] American Cancer Society, “Cancer Facts and Figures, 2012,” 2012. http://www.cancer.org/acs/ groups/content/@epidemio logysurveilance/docume nts/document/acspc-031941.pdf
[2] A. Argiris, M. V. Karamouzis, D. Raben and R. L. Ferris, “Head and Neck Cancer,” Lancet, Vol. 371, No. 9625, 2008, pp. 1695-1709. doi:10.1016/S0140-6736(08)60728-X
[3] B. Ogretmen and Y. A. Hannun, “Biologically Active Sphingolipids in Cancer Pathogenesis and Treatment,” Nature Reviews Molecular Cell Biology, Vol. 4, No. 8, 2004, pp. 604-616. doi:10.1 038/nrc1411
[4] Y. A. Hannun and L. M. Obeid, “Principles of Bioactive Lipid Signalling: Lessons from Sphingolipids,” Nature Reviews Molecular Cell Biology, Vol. 9, No. 2, 2008, pp. 139-150. doi:10.1038/nrm2329
[5] S. Spiegel and S. Milstien, “Sphingosine-1-Phosphate: An Enigmatic Signalling Lipid,” Nature Reviews Molecular Cell Biology, Vol. 4, No. 5, 2003, pp. 397-407. doi:10.1038/nrm1103
[6] O. H. Lee, Y. M. Kim, Y. M. Lee, et al., “Sphingosine 1-Phosphate Induces Angiogenesis: Its Angiogenic Action and Signaling Mechanism in Human Umbilical Vein Endothelial Cells,” Biochemical and Biophysical Research Communications, Vol. 264, No. 3, 1999, pp. 743-750. doi:10.1006/b brc.1999.1586
[7] N. Bergelin, T. Blom, J. Heikkila, et al., “Sphingosine Kinase as an Oncogene: Autocrine Sphingosine 1-Phosphate Modulates ML-1 Thyroid Carcinoma Cell Migration by a Mechanism Dependent on Protein Kinase CAlpha and ERK1/2,” Endocrinology, Vol. 150, No. 5, 2009, pp. 2055-2063. doi:10.1210/en.2008-0625
[8] D. Wang, Z. Zhao, A. Caperell-Grant, et al., “S1P Differentially Regulates Migration of Human Ovarian Cancer and Human Ovarian Surface Epithelial Cells,” Molecular Cancer Therapeutics, Vol. 7, No. 7, 2008, pp. 1993-2002. doi:10.1158/1535-7163.MCT-08-0088
[9] L. Wang and S. M. Dudek, “Regulation of Vascular Permeability by Sphingosine 1-Phosphate,” Microvascular Research, Vol. 77, No. 1, 2009, pp. 39-45. doi:10.1016/j.mvr.2008.09.005
[10] O. Cuvillier, G. Pirianov, B. Kleuser, et al., “Suppression of Ceramide-Mediated Programmed Cell Death by Sphingosine-1-Phosphate,” Nature, Vol. 381, No. 6585, 1996, pp. 800-803. doi:10.1038/381800a0
[11] T. Kohama, A. Olivera, L. Edsall, et al., “Molecular Cloning and Functional Characterization of Murine Sphingosine Kinase,” Journal of Biological Chemistry, Vol. 273, 1998, pp. 23722-23728. doi:10.1074/jbc.273.37.23722
[12] S. M. Mandala, R. Thornton, Z. Tu, et al., “Sphingoid Base 1-Phosphate Phosphatase: A Key Regulator of Sphingolipid Metabolism and Stress Response,” Proceedings of the National Academy of Sciences of USA, Vol. 95, No. 1, 1998, pp. 150-155. doi:10.1073/pnas.95.1.150
[13] A. Olivera, T. Kohama, L. Edsall, et al., “Sphingosine Kinase Expression Increases Intracellular Sphingosine-1-Phosphate and Promotes Cell Growth and Survival,” Journal of Cell Biology, Vol. 147, No. 3, 1999, pp. 545-558. doi:10.1083/jcb.147.3.545
[14] S. Spiegel and S. Milstien, “Functions of the Multifaceted Family of Sphingosine Kinases and Some Close Relatives,” Journal of Biological Chemistry, Vol. 282, No. 4, 2007, pp. 2125-2129. doi:10.1074/jbc.R600028200
[15] T. Kawamori, T. Kaneshiro, M. Okumura, et al., “Role for Sphingosine Kinase 1 in Colon Carcinogenesis,” FASEB Journal, Vol. 23, No. 2, 2009, pp. 405-414. doi:10.1096/fj.08-117572
[16] J. R. Van Brocklyn, C. A. Jackson, D. K. Pearl, M. S. Kotur, P. J. Snyder and T. W. Prior, “Sphingosine Kinase-1 Expression Correlates with Poor Survival of Patients with Glioblastoma Multiforme: Roles of Sphingosine Kinase Isoforms in Growth of Glioblastoma Cell Lines,” Journal of Neuropathology & Experimental Neurology, Vol. 64, No. 8, 2005, pp. 695-705. doi:10.1097/01.jn en.0000175329.59092.2c
[17] M. Vadas, P. Xia, G. McCaughan and J. Gamble, “The Role of Sphingosine Kinase 1 in Cancer: Oncogene or Non-Oncogene Addiction?” Biochimica et Biophysica Acta, Vol. 1781, No. 9, 2008, pp. 442-447.
[18] U. K. Sinha, V. J. Schorn, C. Hochstim, S. B. Chinn, S. Zhu and R. Masood, “Increased Radiation Sensitivity of Head and Neck Squamous Cell Carcinoma with Sphingosine Kinase 1 Inhibition,” Head & Neck, Vol. 33, No. 2, 2010, pp. 178-188.
[19] R. Kolesnick and Z. Fuks, “Radiation and CeramideInduced Apoptosis,” Oncogene, Vol. 22, No. 37, 2003, pp. 5897-5906. doi:10.1038/sj.onc.1206702
[20] X. Deng, X. Yin, R. Allan, et al., “Ceramide Biogenesis Is Required for Radiation-Induced Apoptosis in the Germ Line of C. elegans,” Science, Vol. 322, No. 5898, 2008, pp. 110-115. doi:10.1126/sc ience.1158111
[21] V. E. Nava, O. Cuvillier, L. C. Edsall, et al., “Sphingosine Enhances Apoptosis of Radiation-Resistant Prostate Cancer Cells,” Cancer Research, Vol. 60, No. 16, 2000, pp. 4468-4474.
[22] T. A. Taha, W. Osta, L. Kozhaya, et al., “Down-Regulation of Sphingosine Kinase-1 by DNA Damage: Dependence on Proteases and p53,” The Journal of Biological Chemistry, Vol. 279, No. 19, 2004, pp. 20546-20554. doi:10.1074/jbc.M401259200
[23] A. E. Mahdy, J. C. Cheng, J. Li, et al., “Acid Ceramidase Upregulation in Prostate Cancer Cells Confers Resistance to Radiation: AC Inhibition, a Potential Radiosensitizer,” Molecular Therapy, Vol. 17, No. 3, 2009, pp. 430-438. doi:10.1038/mt.2008.281
[24] K. Shirai, T. Kaneshiro, M. Wada, et al., “A Role of Sphingosine Kinase 1 in Head and Neck Carcinogenesis,” Cancer Prevention Research, Vol. 4, No. 3, 2011, pp. 454-462. doi:10.1158/1940-6207.CAPR-10-0299
[25] R. Masood, I. Roy, S. Zu, et al., “Gold Nanorod-Sphingosine Kinase siRNA Nanocomplexes: A Novel Therapeutic Tool for Potent Radiosensitization of Head and Neck Cancer,” Integrative Biology, Vol. 4, No. 2, 2012, pp. 132-141. doi:10.1039/c1ib00060h
[26] F. Farshadpour, H. Kranenborg, E. V. Caikoen, et al., “Survival Analysis of Head and Neck Squamous Cell Carcinoma: Influence of Smoking and Drinking,” Head & Neck, Vol. 33, No. 6, 2011, pp. 817-823. doi:10.1002/hed.21549
[27] E. M. Sturgis, “The International Head and Neck Cancer Epidemiology Consortium,” Head & Neck, Vol. 33, No. 1, 2011, p. 141. doi:10.1002/hed.21670
[28] M. M. Facchinetti, N. A. Gandini, M. E. Fermento, et al., “The Expression of Sphingosine Kinase-1 in Head and Neck Carcinoma,” Cells Tissues Organs, Vol. 192, No. 5, 2010, pp. 314-324. doi:10.1159/000318173
[29] E. Ruckh?berle, A. Rody, K. Engels, et al., “Microarray Analysis of Altered Sphingolipid Metabolism Reveals Prognostic Significance of Sphingosine Kinase 1 in Breast Cancer,” Breast Cancer Research and Treatment, Vol. 112, No. 1, 2007, pp. 41-52. doi:10.1007/s10549-007-9836-9

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