IJOHNS  Vol.4 No.3 , May 2015
Prognostic and Predictive Protein Biomarkers in Laryngeal Squamous Cell Carcinoma—A Systematic Review
Background: Despite recent advances in clinical management of laryngeal squamous cell carcinoma (LSCC), the overall 5-year survival continues to be poor. Consequently, biomarkers of treatment response will need to be identified. Proteomic strategies are one way to attempt to identify such biomarkers. Methods: The Medline, Embase and Cochrane Library databases were systematically searched until 1st March 2014 using the terms “larynx”, “squamous cell carcinoma”, “proteomic”, and “biomarker”. Articles which met inclusion criteria were assessed for the type of biomarker investigated, the proteomic technique used, and whether any validation had been performed. Results: Six studies identified biomarkers, including UCRP, ceramides, uPA, MT1-MMP, stratifin, transferrin, albumin, S100 calcium-binding protein A9, stathmin, enolase, PLAU, IGFBP7, MMP14, THBS1, and transthyretin. Transferrin was the only biomarker to appear in more than one study. Conclusions: Our review identified several potential biomarkers of outcome in LSCC. Well designed studies will need to further validate their use in the future.

Cite this paper
Kwok, M. and Goodyear, P. (2015) Prognostic and Predictive Protein Biomarkers in Laryngeal Squamous Cell Carcinoma—A Systematic Review. International Journal of Otolaryngology and Head & Neck Surgery, 4, 180-189. doi: 10.4236/ijohns.2015.43031.
[1]   Ferlay, J.S.I., Ervik, M., Dikshit, R., et al. (2013) Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11; GLOBOCAN 2012 v1.0 2013. International Agency for Research on Cancer, Lyon.

[2]   Siegel, R., Ma, J., Zou, Z. and Jemal, A. (2014) Cancer Statistics, 2014. CA: A Cancer Journal for Clinicians, 64, 9-29.

[3]   Shah, J.P., Karnell, L.H., Hoffman, H.T., et al. (1997) Patterns of Care for Cancer of the Larynx in the United States. Archives of Otolaryngology—Head & Neck Surgery, 123, 475-483.

[4]   Mitri, Z., Constantine, T. and O’Regan, R. (2012) The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy. Chemotherapy Research and Practice, 2012, Article ID: 743193.

[5]   Almadori, G., Bussu, F., Cadoni, G., Galli, J., Paludetti, G. and Maurizi, M. (2005) Molecular Markers in Laryngeal Squamous Cell Carcinoma: Towards an Integrated Clinicobiological Approach. European Journal of Cancer, 41, 683-693.

[6]   Almadori, G., Bussu, F. and Paludettii, G. (2006) Predictive Factors of Neck Metastases in Laryngeal Squamous Cell Carcinoma. Towards an Integrated Clinico-Molecular Classification. Acta Otorhinolaryngologica Italica, 26, 326-334.

[7]   Fletcher, A.M., Heaford, A.C. and Trask, D.K. (2008) Detection of Metastatic Head and Neck Squamous Cell Carcinoma Using the Relative Expression of Tissue-Specific Mir-205. Translational Oncology, 1, 202-208.

[8]   Patel, V., Martin, D., Malhotra, R., et al. (2013) DSG3 as a Biomarker for the Ultrasensitive Detection of Occult Lymph Node Metastasis in Oral Cancer Using Nanostructured Immunoarrays. Oral Oncology, 49, 93-101.

[9]   Grandis, J.R. and Tweardy, D.J. (1993) Elevated Levels of Transforming Growth Factor Alpha and Epidermal Growth Factor Receptor Messenger RNA Are Early Markers of Carcinogenesis in Head and Neck Cancer. Cancer Research, 53, 3579-3584.

[10]   Reed, A.L., Califano, J., Cairns, P., et al. (1996) High Frequency of p16 (CDKN2/MTS-1/INK4A) Inactivation in Head and Neck Squamous Cell Carcinoma. Cancer Research, 56, 3630-3633.

[11]   Combes, J.D. and Franceschi, S. (2014) Role of Human Papillomavirus in Non-Oropharyngeal Head and Neck Cancers. Oral Oncology, 50, 370-379.

[12]   Gheit, T., Abedi-Ardekani, B., Carreira, C., Missad, C.G., Tommasino, M. and Torrente, M.C. (2014) Comprehensive Analysis of HPV Expression in Laryngeal Squamous Cell Carcinoma. Journal of Medical Virology, 86, 642-646.

[13]   Bonner, J.A., Harari, P.M., Giralt, J., Azarnia, N., Shin, D.M., Cohen, R.B., et al. (2006) Radiotherapy plus Cetuximab for Squamous-Cell Carcinoma of the Head and Neck. The New England Journal of Medicine, 354, 567-578.

[14]   Bonner, J.A., Harari, P.M., Giralt, J., Cohen, R.B., Jones, C.U., Sur, R.K., et al. (2010) Radiotherapy plus Cetuximab for Locoregionally Advanced Head and Neck Cancer: 5-Year Survival Data from a Phase 3 Randomized Trial, and Relation between Cetuximab-Induced Rash and Survival. The Lancet Oncology, 11, 21-28.

[15]   Rudert, F. (2000) Genomics and Proteomics Tools for the Clinic. Current Opinion in Molecular Therapeutics, 2, 633- 642.

[16]   Celis, J.E. and Gromov, P. (1999) 2D Protein Electrophoresis: Can It Be Perfected? Current Opinion in Biotechnology, 10, 16-21.

[17]   Unlu, M. (1999) Difference Gel Electrophoresis. Bio-chemical Society Transactions, 27, 547-549.

[18]   Cheng, A.J., Chen, L.C., Chien, K.Y., Chen, Y.J., Chang, J.T.C., Wang, H.-M., et al. (2005) Oral Cancer Plasma Tumor Marker Identified with Bead-Based Affinity-Fractionated Proteomic Technology. Clinical Chemistry, 51, 2236- 2244.

[19]   Chapman, K. (2002) The Protein Chip Biomarker System from Ciphergen Biosystems: A Novel Proteomics Platform for Rapid Biomarker Discovery and Validation. Biochemical Society Transactions, 30, 82-87.

[20]   Craven, R.A. and Banks, R.E. (2001) Laser Capture Microdissection and Proteomics: Possibilities and Limitation. Proteomics, 1, 1200-1204.

[21]   Qian, W.J., Jacobs, J.M., Liu, T., Camp II, D.G. and Smith, R.D. (2006) Advances and Challenges in Liquid Chromatography-Mass Spectrometry-Based Proteomics Profiling for Clinical Applications. Molecular & Cellular Proteomics: MCP, 5, 1727-1744.

[22]   Evans, C., Noirel, J., Ow, S.Y., et al. (2012) An Insight into iTRAQ: Where Do We Stand Now? Analytical and Bioanalytical Chemistry, 404, 1011-1027.

[23]   Sewell, D.A., Yuan, C.X. and Robertson, E. (2007) Proteomic Signatures in Laryngeal Squamous Cell Carcinoma. ORL: Journal for Oto-Rhino-Laryngology and Its Related Specialties, 69, 77-84.

[24]   Conrads, T.P., Zhou, M., Petricoin 3rd, E.F., Liotta, L. and Veenstra, T.D. (2003) Cancer Diagnosis Using Proteomic Patterns. Expert Review of Molecular Diagnostics, 3, 411-420.

[25]   Schirle, M., Heurtier, M.A. and Kuster, B. (2013) Profiling Core Proteomes of Human Cell Lines by One-Dimensional PAGE and Liquid Chromatography-Tandem Mass Spectrometry. Molecular & Cellular Proteomics: MCP, 2, 1297- 1305.

[26]   Tanca, A., Pagnozzi, D., Burrai, G.P., Polinas, M., Uzzau, S., Antuofermo, E. and Addis, M.F. (2012) Comparability of Differential Proteomics Data Generated from Paired Archival Fresh-Frozen and Formalin-Fixed Samples by GeLC-MS/MS and Spectral Counting. Journal of Proteomics, 77, 561-576.

[27]   Streckfus, C.F. and Dubinsky, W.P. (2007) Proteomic Analysis of Saliva for Cancer Diagnosis. Expert Review of Proteomics, 4, 329-332.

[28]   Cheng, Y.S., Rees, T. and Wright, J. (2014) A Review of Research on Salivary Biomarkers for Oral Cancer Detection. Clinical and Translational Medicine, 3, 3.

[29]   Ma, Y., Zhang, P., Wang, F. and Qin, H. (2012) Searching for Consistently Reported Up- and Down-Regulated Biomarkers in Colorectal Cancer: A Systematic Review of Proteomic Studies. Molecular Biology Reports, 39, 8483-8490.

[30]   Chi, L.M., Lee, C.W., Chang, K.P., Hao, S.-P., Lee, H.-M., Liang, Y., et al. (2009) Enhanced Interferon Signaling Pathway in Oral Cancer Revealed by Quantitative Proteome Analysis of Microdissected Specimens Using 16O/18O Labeling and Integrated Two-Dimensional LC-ESI-MALDI Tandem MS. Molecular & Cellular Proteomics: MCP, 8, 1453-1474.

[31]   Dowling, P., Wormald, R., Meleady, P., Henry, M., Curran, A. and Clynes, M. (2008) Analysis of the Saliva Proteome from Patients with Head and Neck Squamous Cell Carcinoma Reveals Differences in Abundance Levels of Proteins Associated with Tumour Progression and Metastasis. Journal of Proteomics, 71, 168-175.

[32]   Karahatay, S., Thomas, K., Koybasi, S., Senkal, C.E., ElOjeimy, S., Liu, X., et al. (2007) Clinical Relevance of Ceramide Metabolism in the Pathogenesis of Human Head and Neck Squamous Cell Carcinoma (HNSCC): Attenuation of C18-Ceramide in HNSCC Tumors Correlates with Lymphovascular Invasion and Nodal Metastasis. Cancer Letters, 256, 101-111.

[33]   Sepiashvili, L., Hui, A., Ignatchenko, V., Shi, W., Su, S., Xu, W., et al. (2012) Potentially Novel Candidate Biomarkers for Head and Neck Squamous Cell Carcinoma Identified Using an Integrated Cell Line-Based Discovery Strategy. Molecular & Cellular Proteomics: MCP, 11, 1404-1415.

[34]   Galazis, N., Pang, Y.L., Galazi, M., Haoula, Z., Layfield, R. and Atiomo, W. (2013) Proteomic Biomarkers of Endometrial Cancer Risk in Women with Polycystic Ovary Syndrome: A Systematic Review and Biomarker Database Integration. Gynecological Endocrinology: The Official Journal of the International Society of Gynecological Endocrinology, 29, 638-644.

[35]   Parolini, S., Flagiello, D., Cinquetti, A., Gozzi, R., Cristini, S., Cappiello, J., et al. (1996) Up-Regulation of Urokinase-Type Plasminogen Activator in Squamous Cell Carcinoma of Human Larynx. British Journal of Cancer, 74, 1168-1174.

[36]   Yoshizaki, T., Sato, H., Maruyama, Y., Murono, S., Furukawa, M., Park, C.-S. and Seiki, M. (1997) Increased Expression of Membrane Type 1-Matrix Metalloproteinase in Head and Neck Carcinoma. Cancer, 79, 139-144.

[37]   Donato, R. (2001) S100: A Multigenic Family of Calcium-Modulated Proteins of the EF-Hand Type with Intracellular and Extracellular Functional Roles. The International Journal of Biochemistry & Cell Biology, 33, 637-668.

[38]   Cao, L.Y., Yin, Y., Li, H., Jiang, Y. and Zhang, H.F. (2009) Expression and Clinical Significance of S100A2 and p63 in Esophageal Carcinoma. World Journal of Gastroenterology: WJG, 15, 4183-4188.

[39]   Fuentes, M.K., Nigavekar, S.S., Arumugam, T., Logsdon, C.D., Schmidt, A.M., Park, J.C. and Huang, E.H. (2007) RAGE Activation by S100P in Colon Cancer Stimulates Growth, Migration, and Cell Signaling Pathways. Diseases of the Colon and Rectum, 50, 1230-1240.

[40]   Arumugam, T., Simeone, D.M., Van Golen, K. and Logsdon, C.D. (2005) S100P Promotes Pancreatic Cancer Growth, Survival, and Invasion. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 11, 5356-5364.

[41]   Mahon, P.C., Baril, P., Bhakta, V., Chelala, C., Caulee, K., Harada, T. and Lemoine, N.R. (2007) S100A4 Contributes to the Suppression of BNIP3 Expression, Chemoresistance, and Inhibition of Apoptosis in Pancreatic Cancer. Cancer Research, 67, 6786-6795.

[42]   Pedersen, K.B., Andersen, K., Fodstad, O. and Maelandsmo, G.M. (2004) Sensitization of Interferon-Gamma Induced Apoptosis in Human Osteosarcoma Cells by Extracellular S100A4. BMC Cancer, 4, 52.

[43]   Jenkinson, S.R., Barraclough, R., West, C.R. and Rudland, P.S. (2004) S100A4 Regulates Cell Motility and Invasion in an in Vitro Model for Breast Cancer Metastasis. British Journal of Cancer, 90, 253-262.z

[44]   Lo, J.F., Yu, C.C., Chiou, S.H., Huang, C.Y., Jan, C.I., Lin, S.C., et al. (2011) The Epithelial-Mesenchymal Transition Mediator S100A4 Maintains Cancer-Initiating Cells in Head and Neck Cancers. Cancer Research, 71, 1912-1923.

[45]   Kawai, H., Minamiya, Y. and Takahashi, N. (2011) Prognostic Impact of S100A9 Overexpression in Non-Small Cell Lung Cancer. Tumour Biology: The Journal of the International Society for Oncodevelopmental Biology and Medicine, 32, 641-646.

[46]   Smith, S.L., Gugger, M., Hoban, P., Ratschiller, D., Watson, S.G., Field, J.K., et al. (2004) S100A2 Is Strongly Expressed in Airway Basal Cells, Preneoplastic Bronchial Lesions and Primary Non-Small Cell Lung Carcinomas. British Journal of Cancer, 91, 1515-1524.

[47]   Wang, H., Zhang, Z., Li, R., Ang, K.K., Zhang, H., Caraway, N.P., et al. (2005) Overexpression of S100A2 Protein as a Prognostic Marker for Patients with Stage I Non Small Cell Lung Cancer. International Journal of Cancer, 116, 285- 290.

[48]   Ohuchida, K., Mizumoto, K., Miyasaka, Y., Yu, J., Cui, L., Yamaguchi, H., et al. (2007) Over-Expression of S100A2 in Pancreatic Cancer Correlates with Progression and Poor Prognosis. The Journal of Pathology, 213, 275-282.

[49]   Xiao, M.B., Jiang, F., Ni, W.K., Chen, B.-Y., Lu, C.-H., Li, X.-Y. and Ni, R.-Z. (2012) High Expression of S100A11 in Pancreatic Adenocarcinoma Is an Unfavorable Prognostic Marker. Medical Oncology, 29, 1886-1891.

[50]   Almadori, G., Bussu, F., Galli, J., Rigante, M., Lauriola, L., Michetti, F., et al. (2009) Diminished Expression of S100A2, a Putative Tumour Suppressor, Is an Independent Predictive Factor of Neck Node Relapse in Laryngeal Squamous Cell Carcinoma. Journal of Otolaryngology—Head & Neck Surgery, 38, 16-22.

[51]   Tripathi, S.C., Matta, A., Kaur, J., Grigull, J., Chauhan, S.S., Thakar, A., et al. (2010) Nuclear S100A7 Is Associated with Poor Prognosis in Head and Neck Cancer. PloS ONE, 5, e11939.

[52]   Astrand, R., Unden, J. and Romner, B. (2013) Clinical Use of the Calcium-Binding S100B Protein. Methods in Molecular Biology, 963, 373-384.

[53]   Hartman, K.G., McKnight, L.E., Liriano, M.A. and Weber, D.J. (2013) The Evolution of S100B Inhibitors for the Treatment of Malignant Melanoma. Future Medicinal Chemistry, 5, 97-109.

[54]   Szoke, D. and Panteghini, M. (2012) Diagnostic Value of Transferrin. Clinica Chimica Acta: International Journal of Clinical Chemistry, 413, 1184-1189.

[55]   Sethi, A., Sher, M., Akram, M.R., Karim, S., Khiljee, S., Sajjad, A., et al. (2013) Albumin as a Drug Delivery and Diagnostic Tool and Its Market Approved Products. Acta Poloniae Pharmaceutica, 70, 597-600.

[56]   Chen, J., Chen, L.J., Xia, Y.L., Zhou, H.-C., Yang, R.-B., Wu, W., et al. (2013) Identification and Verification of Transthyretin as a Potential Biomarker for Pancreatic Ductal Adenocarcinoma. Journal of Cancer Research and Clinical Oncology, 139, 1117-1127.

[57]   Lv, S., Gao, J., Zhu, F., Li, Z.S., Gong, Y.F., Xu, G.M. and Ma, L. (2011) Transthyretin, Identified by Proteomics, Is Overabundant in Pancreatic Juice from Pancreatic Carcinoma and Originates from Pancreatic Islets. Diagnostic Cytopathology, 39, 875-881.

[58]   Fleming, C.E., Nunes, A.F. and Sousa, M.M. (2009) Transthyretin: More than Meets the Eye. Progress in Neurobiology, 89, 266-276.

[59]   Mizuno, K. (2013) Signaling Mechanisms and Functional Roles of Cofilin Phosphorylation and Dephosphorylation. Cellular Signalling, 25, 457-469.

[60]   Fernandez, P.M., Patierno, S.R. and Rickles, F.R. (2004) Tissue Factor and Fibrin in Tumor Angiogenesis. Seminars in Thrombosis and Hemostasis, 30, 31-44.

[61]   Desai, S.D., Mao, Y., Sun, M., Li, T.K., Wu, J. and Liu, L.F. (2000) Ubiquitin, SUMO-1, and UCRP in Camptothecin Sensitivity and Resistance. Annals of the New York Academy of Sciences, 922, 306-308.

[62]   Desai, S.D., Wood, L.M., Tsai, Y.C., Hsieh, T.-S., Marks, J.R., Scott, G.L., et al. (2008) ISG15 as a Novel Tumor Biomarker for Drug Sensitivity. Molecular Cancer Therapeutics, 7, 1430-1439.

[63]   Belletti, B. and Baldassarre, G. (2011) Stathmin: A Protein with Many Tasks. New Biomarker and Potential Target in Cancer. Expert Opinion on Therapeutic Targets, 15, 1249-1266.

[64]   Giampietro, C., Luzzati, F., Gambarotta, G., Giacobini, P., Boda, E., Fasolo, A. and Perroteau, I. (2005) Stathmin Expression Modulates Migratory Properties of GN-11 Neurons in Vitro. Endocrinology, 146, 1825-1834.

[65]   Jin, K., Mao, X.O., Cottrell, B., et al. (2004) Proteomic and Immunochemical Characterization of a Role for Stathmin in Adult Neurogenesis. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology, 18, 287-299.

[66]   Chen, D., Yoo, B.K., Santhekadur, P.K., et al. (2011) Insulin-Like Growth Factor-Binding Protein-7 Functions as a Potential Tumor Suppressor in Hepatocellular Carcinoma. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 17, 6693-6701.

[67]   Shersher, D.D., Vercillo, M.S., Fhied, C., Basu, S., Rouhi, O., Mahon, B., et al. (2011) Biomarkers of the Insulin-Like Growth Factor Pathway Predict Progression and Outcome in Lung Cancer. The Annals of Thoracic Surgery, 92, 1805- 1811; Discussion 1811.

[68]   Mignatti, P. and Rifkin, D.B. (1993) Biology and Biochemistry of Proteinases in Tumor Invasion. Physiological Reviews, 73, 161-195.

[69]   Duffy, M.J., Duggan, C., Mulcahy, H.E., McDermott, E.W. and O’Higgins, N.J. (1998) Urokinase Plasminogen Activator: A Prognostic Marker in Breast Cancer Including Patients with Axillary Node-Negative Disease. Clinical Chemistry, 44, 1177-1183.

[70]   Kim, T.D., Song, K.S., Li, G., Choi, H., Park, H.-D., Lim, K., et al. (2006) Activity and Expression of Urokinase-Type Plasminogen Activator and Matrix Metalloproteinases in Human Colorectal Cancer. BMC Cancer, 6, 211.

[71]   Wang, D. and Wang, T. (2005) Expressions and Clinical Significance of Urokinase-Type Activator (uPA) and uPA Receptor (uPAR) in Laryngeal Squamous Cell Carcinoma. Journal of Clinical Otorhinolaryngology, 19, 529-531.

[72]   Wu, H.Y., Shen, X.H., Ni, R.S., Qian, X.Y. and Gao, X. (2009) Expression of E-Cadherin and uPA and Their Prognostic Value in Carcinoma of Human Larynx. Chinese Journal of Otorhinolaryngology Head and Neck Surgery, 44, 1024- 1028.

[73]   Gou, X., Chen, H., Jin, F., Wu, W., Li, Y., Long, J., et al. (2013) Expressions of CD147, MMP-2 and MMP-9 in Laryngeal Carcinoma and Its Correlation with Poor Prognosis. Pathology Oncology Research: POR, Published Online.

[74]   Yang, L., Shang, X., Zhao, X., Lin, Y. and Liu, J. (2012) Correlation Study between OPN, CD44v6, MMP-9 and Distant Metastasis in Laryngeal Squamous Cell Carcinoma. Journal of Clinical Otorhinolaryngology, Head, and Neck Surgery, 26, 989-992.

[75]   Ogretmen, B. and Hannun, Y.A. (2004) Biologically Active Sphingolipids in Cancer Pathogenesis and Treatment. Nature Reviews Cancer, 4, 604-616.

[76]   Koybasi, S., Senkal, C.E., Sundararaj, K., Spassieva, S., Bielawski, J., Osta, W., et al. (2004) Defects in Cell Growth Regulation by C18:0-Ceramide and Longevity Assurance Gene 1 in Human Head and Neck Squamous Cell Carcinomas. The Journal of Biological Chemistry, 279, 44311-44319.

[77]   Senkal, C.E., Ponnusamy, S., Rossi, M.J., Bialewski, J., Sinha, D., Jiang, J.C., et al. (2007) Role of Human Longevity Assurance Gene 1 and C18-Ceramide in Chemotherapy-Induced Cell Death in Human Head and Neck Squamous Cell Carcinomas. Molecular Cancer Therapeutics, 6, 712-722.

[78]   Issaq, H.J., Waybright, T.J. and Veenstra, T.D. (2011) Cancer Biomarker Discovery: Opportunities and Pitfalls in Analytical Methods. Electrophoresis, 32, 967-975.