Salivary Biomarkers in Oral Cancer

  • Prashanth PantaEmail author
  • David T. W. Wong


Saliva is an easily accessible biofluid with immense diagnostic potential in oral cancer. The identification of potential saliva signatures for early, noninvasive detection of oral squamous cell carcinoma (OSCC) lead to early detection, better outcome, and survival. More than 100 biomarkers have shown differential levels in saliva of patients with OSCC. They encompass a large number of proteins which cover cell surface molecules (CD44sol, CA-125, etc.), cytoskeleton fragments (CYFRA 21-1), intracellular proteins (ZNF-510, Mac-2 binding protein), proteases (MMPs) and inflammation-associated proteins (CRP, defensin-1, IL-6, IL-8), and mRNA signatures (IL-8, IL-1B, DUSP1, OAZ1, SAT, and H3F3A) and recently some noncoding RNA (miRNA and circular RNA). Some of these salivary biomarkers (both RNA and proteins) have displayed high sensitivity and specificity and were shown to reflect the underlying molecular characteristics and severity of OSCC. The salivary-mutated and salivary-methylated DNA, HPV-DNA, telomerase level, certain oral microbiota, metabolic and oxidative stress biomarkers, and inorganic ion concentration have also shown biomarker potential. Moreover, the unstable RNA is protected in exosomes, allowing their stable detection and easy quantification. The salivary transcriptome (coding, noncoding RNAs) has also displayed performance in multiethnic cohorts of oral cancer patients. In this chapter, the potential salivary biomarker signatures, corresponding tissue and serum concentration, and their role in OSCC are discussed.


Saliva Biomarkers Oral cancer Liquid biopsy Noninvasive diagnosis Point of care 



Support from the Ronnie James DioStand Up and Shout Cancer Research Fund.


  1. 1.
    Panta P, Venna VR. Salivary RNA signatures in oral cancer detection. Anal Cell Pathol (Amst). 2014;2014:450629.Google Scholar
  2. 2.
    Yu JS, Chen YT, Chiang WF, Hsiao YC, Chu LJ, See LC, et al. Saliva protein biomarkers to detectoral squamous cell carcinoma in a high-risk population in Taiwan. Proc Natl Acad Sci U S A. 2016;113:11549–54.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Wong DT. Towards a simple, saliva-based test for the detection of oral cancer 'oral fluid (saliva), which is the mirror of the body, is a perfect medium to be explored for health and disease surveillance'. Expert Rev Mol Diagn. 2006;6:267–72.CrossRefPubMedGoogle Scholar
  4. 4.
    Martin JL, Wolanin A, Lerner I. Oral Cancer screening. Reducing fear using salivary diagnostics. Dent Today. 2016;35:14.Google Scholar
  5. 5.
    Yanning Ma, Xian Wang, and Hongchuan Jin. Methylated DNA and microRNA in body fluids as biomarkers for cancer detection. Int J Mol Sci. 2013; 14: 10307–10331.Google Scholar
  6. 6.
    Fang WE, Wong DT. Point-of-care platforms for salivary diagnostics. Chin J Dent Res. 2012;15:7–15.Google Scholar
  7. 7.
    Wong DT. Saliva omics. J Am Dent Assoc. 2012;143:19S–24S.CrossRefPubMedGoogle Scholar
  8. 8.
    Wang X, Kaczor-Urbanowicz KE, Wong DT. Salivary biomarkers in cancer detection. Med Oncol. 2017;34:7. Epub 2016 Dec 10CrossRefPubMedGoogle Scholar
  9. 9.
    Kazuya Iwai, Tamiko Minamisawa, Kanako Suga,YasutomoYajima, Kiyotaka Shiba. Isolation of human salivary extracellular vesicles by iodixanol density gradient ultracentrifugation and their characterizations. J Extracell Vesicles. 2016;5:30829.Google Scholar
  10. 10.
    Yoshizawa JM, Schafer CA, Schafer JJ, Farrell JJ, Paster BJ, Wong DT. Salivary biomarkers: toward future clinical and diagnostic utilities. Clin Microbiol Rev. 2013;26:781–91.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Frenkel ES, Ribbeck K. Salivary mucins in host defense and disease prevention. J Oral Microbiol. 2015;7:29759.CrossRefPubMedGoogle Scholar
  12. 12.
    Aps JK, Martens LC. Review: the physiology of saliva and transfer of drugs into saliva. Forensic Sci Int. 2005;150:119–31.CrossRefPubMedGoogle Scholar
  13. 13.
    Ai J, Smith B, Wong DT. Saliva ontology: an ontology-based framework for a Salivaomics Knowledge Base. BMC Bioinformatics. 2010;11:302.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Jenzano JW, Courts NF, Timko DA, Lundblad RL. Levels of glandular kallikrein in whole saliva obtained from patients with solid tumors remote from the oral cavity. J Dent Res. 1986;65:67–70.CrossRefPubMedGoogle Scholar
  15. 15.
    Kaczor-Urbanowicz KE, Carreras-Presas CM, Kaczor T, Michael T, Wei F, Garcia-Godoy F, Wong DTW. Emerging technologies for salivaomics in cancer detection. J Cell Mol Med. 2017;21:640–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Wang A, Wang CP, Michael T, Wong DTW. Oral biofluid biomarker research: current status and emerging Frontiers. Diagnostics (Basel). 2016;6:45.CrossRefGoogle Scholar
  17. 17.
    Nagler RM. Saliva as a tool for oral cancer diagnosis and prognosis. Oral Oncol. 2009;45:1006–10.CrossRefPubMedGoogle Scholar
  18. 18.
    Shah FD, Begum R, Vajaria BN, Patel KR, Patel JB, Shukla SN et al. A review on salivary genomics and proteomics biomarkers in oral Cancer. Ind J Clin Biochem. 2011;26:326–334.Google Scholar
  19. 19.
    Yu-Hsiang Lee, David T. Wong. Saliva: an emerging biofluid for early detection of diseases. Am J Dent. 2009; 22: 241–248.Google Scholar
  20. 20.
    Wu CC, Chu HW, Hsu CW, Chang KP, Liu HP. Saliva proteome profiling reveals potential salivary biomarkers for detection of oral cavity squamous cell carcinoma. Proteomics. 2015;15:3394–404.CrossRefPubMedGoogle Scholar
  21. 21.
    Dhakar N, Astekar M, Jain M, Saawarn S, Saawarn N. Total sialic acid, total protein and total sugar levels in serum and saliva of oral squamous cell carcinoma patients. A case control study Dent Res J (Isfahan). 2013;10:343–7.Google Scholar
  22. 22.
    Shpitzer T, Bahar G, Feinmesser R, Nagler RM. A comprehensive salivary analysis for oral cancer diagnosis. J Cancer Res Clin Oncol. 2007;133:613–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Naor D, Sionov RV, Ish-Shalom D. CD44: structure, function, and association with the malignant process. Adv Cancer Res. 1997;71:241–319.CrossRefPubMedGoogle Scholar
  24. 24.
    Rudzki Z, Jothy S. CD44 and the adhesion of neoplastic cells. Mol Pathol. 1997;50:57–71.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Chen J, Zhou J, Lu J, Xiong H, Shi X, Gong L. Significance of CD44 expression in head and neck cancer: a systemic review and meta-analysis. BMC Cancer. 2014;14:15.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Trapasso S, Allegra E. Role of CD44 as a marker of cancer stem cells in head and neck cancer. Biologics. 2012;6:379–83.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Franzmann EJ, Reategui EP, Carraway KL, Hamilton KL, Weed DT, Goodwin WJ. Salivary soluble CD44: a potential molecular marker for head and neck cancer. Cancer Epidemiol Biomark Prev. 2005;14:735–9.CrossRefGoogle Scholar
  28. 28.
    Franzmann EJ, Reategui EP, Pedroso F, Pernas FG, Karakullukcu BM, Carraway KL, et al. Soluble CD44 is a potential marker for the early detection of head and neck cancer. Cancer Epidemiol Biomark Prev. 2007;16:1348–55.CrossRefGoogle Scholar
  29. 29.
    Franzmann EJ, Reategui EP, Pereira LH, Pedroso F, Joseph D, Allen GO, et al. Salivary protein and solCD44 levels as a potential screening tool for early detection of head and neck squamous cell carcinoma. Head Neck. 2012;34:687–95.CrossRefPubMedGoogle Scholar
  30. 30.
    Elashoff D, Zhou H, Reiss J, Wang J, Henson B, Shen H, et al. Pre-validation of salivary biomarkers for oral Cancer detection. Cancer Epidemiol Biomark Prev. 2012;21:664–72.CrossRefGoogle Scholar
  31. 31.
    Jacobs I, Bast RC Jr. The CA 125 tumour-associated antigen: a review of the literature. Hum Reprod. 1989;4:1–12.CrossRefPubMedGoogle Scholar
  32. 32.
    Balan JJ, Rao RS, Premalatha BR, Patil S. Analysis of tumor marker CA 125 in saliva of normal and oral squamous cell carcinoma patients: a comparative study. J Contemp Dent Pract. 2012;13:671–5.CrossRefPubMedGoogle Scholar
  33. 33.
    Geng XF, Du M, Han JX, Zhang M, Tang XF, Xing RD. Saliva CA125 and TPS levels in patients with oral squamous cell carcinoma. Int J Biol Markers. 2013;28:216–20.CrossRefPubMedGoogle Scholar
  34. 34.
    He H, Chen G, Zhou L, Liu Y. A joint detection of CEA and CA-50 levels in saliva and serum of patients with tumors in oral region and salivary gland. J Cancer Res Clin Oncol. 2009;135:1315–21.CrossRefPubMedGoogle Scholar
  35. 35.
    Varun C, Dineshkumar T, Jayant VS, Rameshkumar A, Rajkumar K, Rajashree P, et al. Salivary Her2/neu levels in differentiation of oral premalignant disorders and oral squamous cell carcinomas. Asian Pac J Cancer Prev. 2015;16:5773–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Barak V, Goike H, Panaretakis KW, Einarsson R. Clinical utility of cytokeratins as tumor markers. Clin Biochem. 2004;37:529–40.CrossRefPubMedGoogle Scholar
  37. 37.
    Zhong LP, Zhu HG, Zhang CP, Chen WT, Zhang ZY. Detection of serum Cyfra 21-1 in patients with primary oral squamous cell carcinoma. Int J Oral Maxillofac Surg. 2007;36:230–4.CrossRefPubMedGoogle Scholar
  38. 38.
    Hsu YP, Hsieh CH, Chien HT, Lai CH, Tsao CK, Liao CT, et al. Serum markers of CYFRA 21-1 and C-reactive proteins in oral squamous cell carcinoma. World J Surg Oncol. 2015;13:253.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Zhong LP, Zhang CP, Zheng JW, Li J, Chen WT, Zhang ZY. Increased Cyfra 21-1 concentration in saliva from primary oral squamous cell carcinoma patients. Arch Oral Biol. 2007;52:1079–87.CrossRefPubMedGoogle Scholar
  40. 40.
    Nagler R, Bahar G, Shpitzer T, Feinmesser R. Concomitant analysis of salivary tumor markers--a new diagnostic tool for oral cancer. Clin Cancer Res. 2006;12:3979–84.CrossRefPubMedGoogle Scholar
  41. 41.
    Rajkumar K, Ramya R, Nandhini G, Rajashree P, Ramesh Kumar A, Nirmala Anandan S. Salivary and serum level of CYFRA 21-1 in oral precancer and oral squamous cell carcinoma. Oral Dis. 2015;21:90–6.CrossRefPubMedGoogle Scholar
  42. 42.
    Sun SS, Hsieh JF, Tsai SC, Ho YJ, Kao CH. Tissue polypeptide specific antigen (TPS) as a tumor marker in nasopharyngeal carcinoma. Anticancer Res. 2000;20:4661–3.PubMedGoogle Scholar
  43. 43.
    Barak V, Meirovitz A, Leibovici V, Rachmut J, Peretz T, Eliashar R, Gross M. The diagnostic and prognostic value of tumor markers (CEA, SCC, CYFRA 21-1, TPS) in head and neck Cancer patients. Anticancer Res. 2015;35:5519–24.PubMedGoogle Scholar
  44. 44.
    Weng LP, Wu CC, Hsu BL, Chi LM, Liang Y, Tseng CP, et al. Secretome-based identification of mac-2 binding protein as a potential oral cancer marker involved in cell growth and motility. J Proteome Res. 2008;7:3765–75.CrossRefPubMedGoogle Scholar
  45. 45.
    Brinkmann O, Kastratovic DA, Dimitrijevic MV, Konstantinovic VS, Jelovac DB, Antic J, et al. Oral squamous cell carcinoma detection by salivary biomarkers in a Serbian population. Oral Oncol. 2011;47:51–5.CrossRefPubMedGoogle Scholar
  46. 46.
    Jen J, Wang YC. Zinc finger proteins in cancer progression. J Biomed Sci. 2016;23:53.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Jou YJ, Lin CD, Lai CH, Tang CH, Huang SH, Tsai MH, et al. Salivary zinc finger protein 510 peptide as a novel biomarker for detection of oral squamous cell carcinoma in early stages. Clin Chim Acta. 2011;412:1357–65.CrossRefPubMedGoogle Scholar
  48. 48.
    Gualtero DF, Suarez Castillo A. Biomarkers in saliva for the detection of oral squamous cell carcinoma and their potential use for early diagnosis: a systematic review. Acta Odontol Scand. 2016;74:170–7.CrossRefPubMedGoogle Scholar
  49. 49.
    Thomas GT, Lewis MP, Speight PM. Matrix metalloproteinases and oral cancer. Oral Oncol. 1999;35:227–33.CrossRefPubMedGoogle Scholar
  50. 50.
    Stott-Miller M, Houck JR, Lohavanichbutr P, Mendéz E, Upton MP, Futran ND, et al. Tumor and salivary matrix metalloproteinase levels are strong diagnostic markers of oral squamous cell carcinoma. Cancer Epidemiol Biomark Prev. 2011;20:2628–36.CrossRefGoogle Scholar
  51. 51.
    Venugopal A, Uma Maheswari TN. Expression of matrix metalloproteinase-9 in oral potentially malignant disorders: a systematic review. J Oral Maxillofac Pathol. 2016;20:474–9.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Russo N, Bellile E, Murdoch-Kinch CA, Liu M, Eisbruch A, Wolf GT, et al. Cytokines in saliva increase in head and neck cancer patients after treatment. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;122:483–490.e1.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Arellano-Garcia ME, Hu S, Wang J, Henson B, Zhou H, Chia D, et al. Multiplexed immunobead-based assay for detection of oral cancer protein biomarkers in saliva. Oral Dis. 2008;14:705–12.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    St John MA, Li Y, Zhou X, Denny P, Ho CM, Montemagno C, et al. Interleukin 6 and interleukin 8 as potential biomarkers for oral cavity and oropharyngeal squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 2004;130:929–35.CrossRefPubMedGoogle Scholar
  55. 55.
    ÉvaCsősz PL, Kalló G, Márkus B, Emri M, Szabó A, et al. Proteomics investigation of OSCC-specific salivary biomarkers in a Hungarian population highlights the importance of identification of population-tailored biomarkers. PLoS One. 2017;12:e0177282.CrossRefGoogle Scholar
  56. 56.
    Gleber-Netto FO, Yakob M, Li F, Feng Z, Dai J, Kao HK, Chang YL, Chang KP, Wong DT. Salivary biomarkers for detection of oral squamous cell carcinoma in a Taiwanese population. Clin Cancer Res. 2016;22:3340–7.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Tai SF, Chien H-T, Young C-K, Tsao C-K, de Pablo A, Fan K-H, et al. Roles of preoperative C-reactive protein are more relevant in buccal cancer than other subsites. World J Surg Oncol. 2017;15:47.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Park H-C, Kim M-Y, Kim C-H. C-reactive protein/albumin ratio as prognostic score in oral squamous cell carcinoma. J Korean Assoc Oral Maxillofac Surg. 2016;42:243–50.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Mizukawa N, Sugiyama K, Fukunaga J, Ueno T, Mishima K, Takagi S, Sugahara T. Defensin-1, a peptide detected in the saliva of oral squamous cell carcinoma patients. Anticancer Res. 1998;18:4645–9.PubMedGoogle Scholar
  60. 60.
    Abiko Y, Nishimura M, Kaku T. Defensins in saliva and the salivary glands. Med Electron Microsc. 2003;36:247–52.CrossRefPubMedGoogle Scholar
  61. 61.
    Mizukawa N, Sugiyama K, Ueno T, Mishima K, Takagi S, Sugahara T. Levels of human defensin-1, an antimicrobial peptide, in saliva of patients with oral inflammation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;87:539–43.CrossRefPubMedGoogle Scholar
  62. 62.
    Mizukawa N, Sugiyama K, Ueno T, Mishima K, Takagi S, Sugahara T. Defensin-1, an antimicrobial peptide present in the saliva of patients with oral diseases. Oral Dis. 1999;5:139–42.CrossRefPubMedGoogle Scholar
  63. 63.
    de Jong EP, Xie H, Onsongo G, Stone MD, Chen XB, Kooren JA, et al. Quantitative proteomics reveals myosin and actin as promising saliva biomarkers for distinguishing pre-malignant and malignant oral lesions. PLoS One. 2010;5:e11148.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Tavassoli M, Brunel N, Maher R, Johnson NW, Soussi T. p53 antibodies in the saliva of patients with squamous cell carcinoma of the oral cavity. Int J Cancer. 1998;78:390–1.CrossRefPubMedGoogle Scholar
  65. 65.
    Castelli M, Cianfriglia F, Manieri A, Palma L, Pezzuto RW, Falasca G, et al. Anti-p53 and anti-heat shock proteins antibodies in patients with malignant or pre-malignant lesions of the oral cavity. Anticancer Res. 2001;21:753–8.PubMedGoogle Scholar
  66. 66.
    Ralhan R, Nath N, Agarwal S, Mathur M, Wasylyk B, Shukla NK. Circulating p53 antibodies as early markers of oral cancer: correlation with p53 alterations. ClinCancer Res. 1998;4:2147–52.Google Scholar
  67. 67.
    Jasim H, Olausson P, Hedenberg-Magnusson B, Ernberg M, Ghafouri B. The proteomic profile of whole and glandular saliva in healthy pain-free subjects. Sci Rep. 2016;6:39073.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Walz A, Stühler K, Wattenberg A, Hawranke E, Meyer HE, Schmalz G, et al. Proteome analysis of glandular parotid and submandibular-sublingual saliva in comparison to whole human saliva by two-dimensional gel electrophoresis. Proteomics. 2006;6:1631–9.CrossRefPubMedGoogle Scholar
  69. 69.
    Szanto I, Mark L, Bona A, Maasz G, Sandor B, Gelencser G, et al. High-throughput screening of saliva for early detection of oral cancer: a pilot study. Technol Cancer Res Treat. 2012;11:181–8.CrossRefPubMedGoogle Scholar
  70. 70.
    Majem B, Rigau M, Reventós J, Wong DT. Non-coding RNAs in saliva: emerging biomarkers for molecular diagnostics. Int J Mol Sci. 2015;16:8676–98.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Jiang WP, Wang Z, Xu LX, Peng X, Chen F. Diagnostic model of saliva peptide finger print analysis of oral squamous cell carcinoma patients using weak cation exchange magnetic beads. Biosci Rep. 2015; 35.pii: e00211.Google Scholar
  72. 72.
    Alicia D. Powers, Sean P. Palecek. Protein analytical assays for diagnosing, monitoring, and choosing treatment for cancer patients. J Healthc Eng. 2012;3:503–34.CrossRefGoogle Scholar
  73. 73.
    Ardito F, Perrone D, Cocchi R, Lo Russo L, DE Lillo A, Gianna tempo G, et al. Novel possibilities in the study of the salivary proteomic profile using SELDI-TOF/MS technology. Oncol Lett. 2016;11:1967–72.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Kawahara R, Bollinger JG, Rivera C, Ribeiro ACP, Brandão TB, Leme AFP, et al. A targeted proteomic strategy for the measurement of oral cancer candidate biomarkers in human saliva. Proteomics. 2016;16:159–73.CrossRefPubMedGoogle Scholar
  75. 75.
    Aziz S, Ahmed SS, Ali A, Khan FA, Zulfiqar G, Iqbal J, et al. Salivary immunosuppressive cytokines IL-10 and IL-13 are significantly elevated in oral squamous cell carcinoma patients. Cancer Investig. 2015;33:318–28.CrossRefGoogle Scholar
  76. 76.
    Vandooren J, Geurts N, Martens E, Van den Steen PE, Opdenakker G. Zymography methods for visualizing hydrolytic enzymes. Nat Methods. 2013;10:211–20.CrossRefPubMedGoogle Scholar
  77. 77.
    Singh RD, Haridas N, Patel JB, Shah FD, Shukla SN, Shah PM, Patel PS. Matrix Metalloproteinases and their inhibitors: correlation with invasion and metastasis in oral Cancer. Indian J Clin Biochem. 2010;25:250–9.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Spielmann N, Ilsley D, Gu J, Lea K, Brockman J, Heater S, et al. The human salivary RNA transcriptome revealed by massively parallel sequencing. Clin Chem. 2012;58:1314–21.CrossRefPubMedGoogle Scholar
  79. 79.
    Ainsztein AM, Brooks PJ, Dugan VG, Ganguly A, Guo M, Howcroft TK, et al. The NIH extracellular RNA communication consortium. J Extracell Vesicles. 2015;4:27493.CrossRefPubMedGoogle Scholar
  80. 80.
    Laurent LC, Abdel-Mageed AB, Adelson PD, Arango J, Balaj L, Breakefield X, et al. Meeting report: discussions and preliminary findings on extracellular RNA measurement methods from laboratories in the NIH extracellular RNA communication consortium. J Extracell Vesicles. 2015;4:26533.CrossRefPubMedGoogle Scholar
  81. 81.
    Bahn JH, Zhang Q, Li F, Chan TM, Lin X, Kim Y, et al. The landscape of microRNA, Piwi-interacting RNA, and circular RNA in human saliva. Clin Chem. 2015;61:221–30.CrossRefGoogle Scholar
  82. 82.
    Li Y, St John MA, Zhou X, Kim Y, Sinha U, Jordan RC, et al. Salivary transcriptome diagnostics for oral cancer detection. Clin Cancer Res. 2004;10:8442–50.CrossRefPubMedGoogle Scholar
  83. 83.
    Li Y, Elashoff D, Oh M, Sinha U, St John MA, Zhou X, Abemayor E, Wong DT. Serum circulating human mRNA profiling and its utility for oral cancer detection. J Clin Oncol.2006; 24:1754–1760.Google Scholar
  84. 84.
    Adami GR, Adami AJ. Looking in the mouth for noninvasive gene expression-based methods to detect oral, oropharyngeal, and systemic cancer. ISRN Oncol 2012;2012:931301.Google Scholar
  85. 85.
    Martin JL, Gottehrer N, Zalesin H, Hoff PT, Shaw M, Clarkson JH, et al. Evaluation of salivary transcriptome markers for the early detection of oral squamous cell cancer in a prospective blinded trial. Compend Contin Educ Dent. 2015;36:365–73.PubMedGoogle Scholar
  86. 86.
    Martin JL. Validation of reference genes for oral Cancer detection panels in a prospective blinded cohort. PLoS One. 2016;11:e0158462.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Modi WS, Dean M, Seuanez HN, Mukaida N, Matsushima K, O'Brien SJ. Monocyte-derived neutrophil chemotactic factor (MDNCF/IL-8) resides in a gene cluster along with several other members of the platelet factor 4 gene superfamily. Hum Genet. 1990;84:185–7.CrossRefPubMedGoogle Scholar
  88. 88.
    Yumoto H, Nakae H, Fujinaka K, Ebisu S, Matsuo T. Interleukin-6 (IL-6) and IL-8 are induced in human oral epithelial cells in response to exposure to period ontopathic Eikenella corrodens. Infect Immun. 1999;67:384–94.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Yamazaki K, Nakajima T, Gemmell E, Polak B, Seymour GJ, Hara K. IL-4- and IL-6-producing cells in human periodontal disease tissue. J Oral Pathol Med. 1994;23:347–53.CrossRefPubMedGoogle Scholar
  90. 90.
    Keyse SM, Emslie EA. Oxidative stress and heat shock induce a human gene encoding a protein-tyrosine phosphatase. Nature. 1992;359:644–7.CrossRefPubMedGoogle Scholar
  91. 91.
    Martell KJ, Kwak S, Hakes DJ, Dixon JE, Trent JM. Chromosomal localization of four human VH1-like protein-tyrosine phosphatases. Genomics. 1994;22:462–4.CrossRefPubMedGoogle Scholar
  92. 92.
    Tanoue T, Yamamoto T, Maeda R, Nishida E. A Novel MAPK phosphatase MKP-7 acts preferentially on JNK/SAPK and p38 alpha and beta MAPKs. J Biol Chem. 200; 276: 26629–39.Google Scholar
  93. 93.
    Slack DN, Seternes OM, Gabrielsen M, Keyse SM. Distinct binding determinants for ERK2/p38alpha and JNK map kinases mediate catalytic activation and substrate selectivity of map kinase phosphatase-1. J Biol Chem. 2001;276:16491–500.CrossRefPubMedGoogle Scholar
  94. 94.
    Khor GH, Froemming GR, Zain RB, Abraham MT, Omar E, Tan SK, et al. DNA methylation profiling revealed promoter Hypermethylation-induced silencing of p16, DDAH2 and DUSP1 in primary oral squamous cell carcinoma. Int J Med Sci. 2013;10:1727–39.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Wang X, Jiang L. Effects of ornithine decarboxylase antizyme 1 on the proliferation and differentiation of human oral cancer cells. Int J Mol Med. 2014;34:1606–12.CrossRefPubMedGoogle Scholar
  96. 96.
    Cheng YS, Jordan L, Rees T, Chen HS, Oxford L, Brinkmann O, Wong D. Levels of potential oral cancer salivary mRNA biomarkers in oral cancer patients in remission and oral lichen planus patients. ClinOral Investig. 2014;18:985–93.Google Scholar
  97. 97.
    Tsuji T, Katsurano M, Ibaragi S, Shima K, Sasaki A, Hu GF. Ornithine decarboxylase antizyme upregulates DNA-dependent protein kinase and enhances the nonhomologous end-joining repair of DNA double-strand breaks in human oral cancer cells. Biochemistry. 2007;46:8920–32.CrossRefPubMedGoogle Scholar
  98. 98.
    Prica F, Radon T, Cheng Y, Crnogorac-Jurcevic T. The life and works of S100P - from conception to cancer. Am J Cancer Res. 2016;6:562–76.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Heil A, Nazmi AR, Koltzscher M, Poeter M, Austermann J, Assard N, et al. S100P is a novel interaction partner and regulator of IQGAP1. J Biol Chem. 2011;286:7227–38.CrossRefPubMedGoogle Scholar
  100. 100.
    Kupferman ME, Patel V, Sriuranpong V, Amornphimoltham P, Jasser SA, Mandal M, et al. Molecular analysis of anoikis resistance in oral cavity squamous cell carcinoma. Oral Oncol. 2007;43:440–54.CrossRefPubMedGoogle Scholar
  101. 101.
    Cheng YL, Jordan L, Chen HS, Kang D, Oxford L, Plemons J, et al. Chronic periodontitis can affect the levels of potential oral cancer salivary mRNA biomarkers. J Periodontal Res. 2017;52:428–37.Google Scholar
  102. 102.
    Xiao L, Celano P, Mank AR, Griffin C, Jabs EW, Hawkins AL, et al. Structure of the human spermidine/spermine N1-acetyltransferase gene (exon/intron gene organization and localization to Xp22.1). Biochem Biophys Res Commun. 1992;187:1493–502.CrossRefPubMedGoogle Scholar
  103. 103.
    Coleman CS, Pegg AE. Polyamine analogues inhibit the ubiquitination of spermidine/spermine N1-acetyltransferase and prevent its targeting to the proteasome for degradation. Biochem J. 2001;358:137–45.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Zhang Y, Reinberg D. Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev. 2001;15:2343–60.CrossRefPubMedGoogle Scholar
  105. 105.
    Yuen BTK, Knoepfler PS. Histone H3.3 mutations: a variant path to cancer. Cancer Cell. 2013;24:567–74.Google Scholar
  106. 106.
    Liao PH, Chang YC, Huang MF, Tai KW, Chou MY. Mutation of p53 gene codon 63 in saliva as a molecular marker for oral squamous cell carcinoma. Oral Oncol. 2000;36:272–6.CrossRefPubMedGoogle Scholar
  107. 107.
    Mattick JS. Non-coding RNAs: the architects of eukaryotic complexity. EMBO Rep. 2001;2:986–91.CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Wong DT. Salivary extracellular noncoding RNA: emerging biomarkers for molecular diagnostics. Clin Ther. 2015;37:540–51.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Felekkis K, Touvana E. ChStefanou, and C deltas microRNAs: a newly described class of encoded molecules that play a role in health and disease. Hippokratia. 2010;14:236–40.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Tian X, Chen Z, Shi S, Wang X, Wang W, Li N, Wang J. Clinical diagnostic implications of body fluid MiRNA in oral squamous cell carcinoma: a meta-analysis. Medicine (Baltimore). 2015;94:e1324.CrossRefGoogle Scholar
  111. 111.
    Park NJ, Zhou H, Elashoff D, Henson BS, Kastratovic DA, Abemayor E, Wong DT. Salivary microRNA: discovery, characterization, and clinical utility for oral cancer detection. Clin Cancer Res. 2009;15:5473–7.CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Liu CJ, Lin SC, Yang CC, Cheng HW, Chang KW. Exploiting salivary miR-31 as a clinical biomarker of oral squamous cell carcinoma. Head Neck. 2012;34:219–24.CrossRefPubMedGoogle Scholar
  113. 113.
    Liu CJ, Kao SY, Tu HF, Tsai MM, Chang KW, Lin SC. Increase of microRNA miR-31 level in plasma could be a potential marker of oral cancer. Oral Dis. 2010;16:360.CrossRefPubMedGoogle Scholar
  114. 114.
    Zahran F, Ghalwash D, Shaker O, Al-Johani K, Scully C. Salivary microRNAs in oral cancer. Oral Dis. 2015;21:739–47.CrossRefPubMedGoogle Scholar
  115. 115.
    Momen-Heravi F, Trachtenberg AJ, Kuo WP, Cheng YS. Genomewide study of salivary MicroRNAs for detection of oral Cancer. J Dent Res. 2014;93:86S–93S.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Jessica A. Weber, David H. Baxter, Shile Zhang, David Y. Huang, Kuo How Huang, Ming Jen Lee, et al. The MicroRNA spectrum in 12 body fluids. Clin Chem. 2010; 56: 1733–1741.Google Scholar
  117. 117.
    Qu S, Zhong Y, Shang R, Zhang X, Song W, Kjems J, Li H. The emerging landscape of circular RNA in life processes. RNA Biol. 2016 Aug;11:1–8.Google Scholar
  118. 118.
    Qu S, Yang X, Li X, Wang J, Gao Y, Shang R. Circular RNA: a new star of noncoding RNAs. Cancer Lett. 2015;365:141–8.CrossRefPubMedGoogle Scholar
  119. 119.
    Zhang Y, Zhang XO, Chen T, Xiang JF, Yin QF, Xing YH, Zhu S, Yang L, Chen LL. Circular intronic long noncoding RNAs. Mol Cell. 2013;51:792–806.CrossRefPubMedGoogle Scholar
  120. 120.
    Meng S, Zhou H, Feng Z, Zihao X, Tang Y, Li P, Minghua W. CircRNA: functions and properties of a novel potential biomarker for cancer. Mol Cancer. 2017;16:94.CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Dudekula DB, Panda AC, Grammatikakis I, De S, Abdelmohsen K, Gorospe M. CircInteractome: A web tool for exploring circular RNAs and their interacting proteins and microRNAs. 2016; 13:34–42.Google Scholar
  122. 122.
    Wang F. Adil J Nazarali, Shaoping Ji. Circular RNAs as potential biomarkers for cancer diagnosis and therapy Am J Cancer Res. 2016;6:1167–76.PubMedGoogle Scholar
  123. 123.
    Jingqiu Li, Jie Yang, Ping Zhou, Yanping Le, Chengwei Zhou, Shaomin Wang, et al. Circular 44RNAs in cancer: novel insights into origins, properties, functions and implications. Am J Cancer Res. 2015; 5: 472–480.Google Scholar
  124. 124.
    Yu SY, Wang YP, Chang JY, Shen WR, Chen HM, Chiang CP. Increased expression of 44MCM5 is significantly associated with aggressive progression and poor prognosis of oral squamous cell carcinoma. J Oral Pathol Med. 2014;43:344–9.CrossRefPubMedGoogle Scholar
  125. 125.
    Chen L, Zhang S, Wu J, Cui J, Zhong L, Zeng L, Ge S. circRNA_100290 plays a role in oral cancer by functioning as a sponge of the miR-29 family. Oncogene. 2017;36:4551–61.Google Scholar
  126. 126.
    Palanisamy V, Wong DT. Transcriptomic analyses of saliva. Methods Mol Biol. 2010;666:43–51.CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Yoshizawa JM, Wong DTW. Salivary MicroRNAs and oral Cancer detection. Methods Mol Biol. 2013;936:313–24.CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Abdulmajeed AA, Farah CS. Gene expression profiling for the purposes of biomarker discovery in oral potentially malignant lesions: a systematic review. Clin Med Insights Oncol. 2013;7:279–90.CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Méndez E, Cheng C, Farwell DG, Ricks S, Agoff SN, Futran ND, et al. Transcriptional expression profiles of oral squamous cell carcinomas. Cancer. 2002;95:1482–94.CrossRefPubMedGoogle Scholar
  130. 130.
    Maskos U, Southern EM. Oligonucleotide hybridizations on glass supports: a novel linker for oligonucleotide synthesis and hybridization properties of oligonucleotides synthesised in situ. Nucleic Acids Res. 1992;20:1679–84.CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Li G, Li X, Yang M, Lvzi X, Deng S, Ran L. Prediction of biomarkers of oral squamous cell carcinoma using microarray technology. Sci Rep. 2017;7:42105.CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Shalon D, Smith SJ, Brown PO. A DNA microarray system for analyzing complex DNA samples using two-color fluorescent probe hybridization. Genome Res. 1996;6:639–45.CrossRefPubMedGoogle Scholar
  133. 133.
    Wu MY, Dai DQ, Zhang XF, Zhu Y. Cancer subtype discovery and biomarker identification via a new robust network clustering algorithm. PLoS One. 2013;8:e66256.CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP, et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science. 1999;286:531–7.CrossRefPubMedGoogle Scholar
  135. 135.
    Kuo WP, Hasina R, Ohno-Machado L, Lingen MW. Classification and identification of genes associated with oral cancer based on gene expression profiles. A preliminary study. N Y State Dent J. 2003;69:23–6.PubMedGoogle Scholar
  136. 136.
    Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44–57.CrossRefPubMedGoogle Scholar
  137. 137.
    Ramaswamy S, Tamayo P, Rifkin R, Mukherjee S, Yeang CH, Angelo M, et al. Multiclass cancer diagnosis using tumor gene expression signatures. Proc Natl Acad Sci U S A. Google Scholar
  138. 138.
    Heid CA, Stevens J, Livak KJ, Williams PM. Real time quantitative PCR. Genome Res. 1996;6:986–94.CrossRefPubMedGoogle Scholar
  139. 139.
    Antonov J, Goldstein DR, Oberli A, Baltzer A, Pirotta M, Fleischmann A, et al. Reliable gene expression measurements from degraded RNA by quantitative real-time PCR depend on short amplicons and a proper normalization. Lab Investig. 2005;85:1040–50.CrossRefPubMedGoogle Scholar
  140. 140.
    Wong ML, Medrano JF. Real-time PCR for mRNA quantitation. BioTechniques. 2005;39:75–85.CrossRefGoogle Scholar
  141. 141.
    Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 2001;25:402–8.CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Dhanasekaran S, Doherty TM, Kenneth J; TB Trials Study Group. Comparison of different standards for real-time PCR-based absolute quantification. J Immunol Methods. 2010;354:34–39.Google Scholar
  143. 143.
    Lin X, Lo H-C, Wong DTW, Xiao X. Noncoding RNAs in human saliva as potential disease biomarkers. Front Genet. 2015;6:175.CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Bonne NJ, Wong DT. Salivarybiomarkerdevelopment using genomic, proteomic and metabolomic approaches. Genome Med. 2012;4:82.CrossRefPubMedPubMedCentralGoogle Scholar
  145. 145.
    Shendure J. The beginning of the end for microarrays? Nat Methods. 2008;5:585.CrossRefPubMedGoogle Scholar
  146. 146.
    Costa V, Aprile M, Esposito R, Ciccodicola A. RNA-Seq and human complex diseases: recent accomplishments and future perspectives. Eur J Hum Genet. 2013;21:134–42.CrossRefPubMedGoogle Scholar
  147. 147.
    Danielson KM, Rubio R, Abderazzaq F, Das S, Wang YE. High throughput sequencing of extracellular RNA from human plasma. PLoS One. 2017;12:e0164644.CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Majem B, Li F, Sun J, Wong DT. RNA sequencing analysis of salivary extracellular RNA. Methods Mol Biol. 2017;1537:17–36.CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Steven R. Head, H. Kiyomi Komori, Sarah A. LaMere, Thomas Whisenant, Filip Van Nieuwerburgh, Daniel R. Salomon. Library construction for next-generation sequencing: Overviews and challenges. Biotechniques. 2014; 56: 61–passim.Google Scholar
  150. 150.
    Podnar J, Deiderick H, Huerta G, Hunicke-Smith S. Next-generation sequencing RNA-Seq library construction. Curr Protoc Mol Biol. 2014;106:4.21.1–19.CrossRefGoogle Scholar
  151. 151.
    Shore S, Henderson JM, Lebedev A, Salcedo MP, Zon G, McCaffrey AP, et al. Small RNA library preparation method for next-generation sequencing using chemical modifications to prevent adapter dimer formation. PLoS One. 2016;11:e0167009.CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Ozsolak F, Milos PM. RNA sequencing: advances, challenges and opportunities. Nat Rev Genet. 2011;12:87–98.CrossRefPubMedGoogle Scholar
  153. 153.
    Yuxuan Wang, Simeon Springer, Carolyn L. Mulvey, Natalie Silliman, Joy Schaefer, Mark Sausen, et al. Detection of somatic mutations and HPV in the saliva and plasma of patients with head and neck squamous cell carcinomas. Sci Transl Med. 2015; 7: 293ra104.Google Scholar
  154. 154.
    Chattopadhyay E, De Sarkar N, Singh R, Ray A, Roy R, Paul RR, et al. Genome-wide mitochondrial DNA sequence variations and lower expression of OXPHOS genes predict mitochondrial dysfunction in oral cancer tissue. Tumour Biol. 2016;37:11861–71.CrossRefPubMedGoogle Scholar
  155. 155.
    Dasgupta S, Koch R, Westra WH, Califano JA, Ha PK, Sidransky D, et al. Mitochondrial DNA mutation in normal margins and tumors of recurrent head and neck squamous cell carcinoma patients. Cancer Prev Res (Phila). 2010;3:1205–11.CrossRefGoogle Scholar
  156. 156.
    Jiang WW, Rosenbaum E, Mambo E, Zahurak M, Masayesva B, Carvalho AL, et al. Decreased mitochondrial DNA content in posttreatment salivary rinses from head and neck cancer patients. Clin Cancer Res. 2006;12:1564–9.CrossRefPubMedGoogle Scholar
  157. 157.
    Hu L. XinyueYao, and Yi Shen. Altered mitochondrial DNA copy number contributes to human cancer risk: evidence from an updated meta-analysis Sci Rep. 2016;6:35859.PubMedGoogle Scholar
  158. 158.
    Lin JC, Wang CC, Jiang RS, Wang WY, Liu SA. Impact of somatic mutations in the D-loop of mitochondrial DNA on the survival of oral squamous cell carcinoma patients. PLoS One. 2015;10:e0124322.CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Mondal R, Ghosh SK. Accumulation of mutations over the complete mitochondrial genome in tobacco-related oral cancer from Northeast India. Mitochondrial DNA. 2013;24:432–9.CrossRefPubMedGoogle Scholar
  160. 160.
    Lièvre A, Blons H, Houllier AM, Laccourreye O, Brasnu D, Beaune P, et al. Clinicopathological significance of mitochondrial D-loop mutations in head and neck carcinoma. Br J Cancer. 2006;94:692–7.CrossRefPubMedPubMedCentralGoogle Scholar
  161. 161.
    Fliss MS, Usadel H, Caballero OL, Wu L, Buta MR, Eleff SM, et al. Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science. 2000;287:2017–9.CrossRefPubMedGoogle Scholar
  162. 162.
    Mondal R, Ghosh SK, Choudhury JH, Seram A, Sinha K, Hussain M, et al. Mitochondrial DNA copy number and risk of oral Cancer: a report from Northeast India. PLoS One. 2013;8:e57771.CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Chatterjee A, Dasgupta S, Sidransky D. Mitochondrial subversion in Cancer. CancerPrev Res (Phila). 2011;4:638–54.CrossRefGoogle Scholar
  164. 164.
    Jiang WW, Masayesva B, Zahurak M, Carvalho AL, Rosenbaum E, Mambo E, et al. Increased mitochondrial DNA content in saliva associated with head and neck cancer. Clin Cancer Res. 2005;11:2486–91.CrossRefPubMedGoogle Scholar
  165. 165.
    Maitra A, Cohen Y, Gillespie SE, Mambo E, Fukushima N, Hoque MO, et al. The human MitoChip: a high-throughput sequencing microarray for mitochondrial mutation detection. Genome Res. 2004;14:812–9.CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Marquis J, Lefebvre G, Kourmpetis YAI, Kassam M, Ronga F, De Marchi U, et al. MitoRS, a method for high throughput, sensitive, and accurate detection of mitochondrial DNA heteroplasmy. BMC Genomics. 2017;18:326.CrossRefPubMedPubMedCentralGoogle Scholar
  167. 167.
    Sukhija H, Krishnan R, Balachander N, Raghavendhar K, Ramadoss R, Sen S. C-deletion in exon 4 codon 63 of p53 gene as a molecular marker for oral squamous cell carcinoma: a preliminary study. Contemp Clin Dent. 2015;6:S227–34.CrossRefPubMedPubMedCentralGoogle Scholar
  168. 168.
    Sun W, Zaboli D, Liu Y, Arnaoutakis D, Khan T, Wang H, et al. Comparison of promoter Hypermethylation pattern in salivary rinses collected with and without an exfoliating brush from patients with HNSCC. PLoS One. 2012;7:e33642.CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Righini CA, de Fraipont F, Timsit JF, Faure C, Brambilla E, Reyt E, et al. Tumor-specific methylation in saliva: a promising biomarker for early detection of head and neck cancer recurrence. Clin Cancer Res. 2007;13:1179–85.CrossRefPubMedGoogle Scholar
  170. 170.
    Rosas SL, Koch W, da Costa Carvalho MG, Wu L, Califano J, Westra W, et al. Promoter hypermethylation patterns of p16, O6-methylguanine-DNA-methyltransferase, and death-associated protein kinase in tumors and saliva of head and neck cancer patients. Cancer Res. 2001;61:939–42.PubMedGoogle Scholar
  171. 171.
    Shaw RJ, Akufo-Tetteh EK, Risk JM, Field JK, Liloglou T. Methylation enrichment pyrosequencing: combining the specificity of MSP with validation by pyrosequencing. Nucleic Acids Res. 2006;34:e78.CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    Viet CT, Jordan RC, Schmidt BL. DNA promoter hypermethylation in saliva for the early diagnosis of oral cancer. J Calif Dent Assoc. 2007; 35: 844–9.Google Scholar
  173. 173.
    Dmitry A Ovchinnikov, Matthew A Cooper, Pratibala Pandit, William B Coman, Justin J Cooper-White, Patricia Keith, et al. Tumor-suppressor gene promoter hypermethylation in saliva of head and neck cancer patients. Transl Oncol. 2012; 5: 321–326.Google Scholar
  174. 174.
    Matthews AM, Kaur H, Dodd M, D'Souza J, Liloglou T, Shaw RJ, et al. Saliva collection methods for DNA biomarker analysis in oral cancer patients. Br J Oral Maxillofac Surg. 2013;51:394–8.CrossRefPubMedGoogle Scholar
  175. 175.
    Boscolo-Rizzo P, Da Mosto MC, Rampazzo E, Giunco S, Del Mistro A, Menegaldo A, et al. Telomeres and telomerase in head and neck squamous cell carcinoma: from pathogenesis to clinical implications. Cancer Metastasis Rev. 2016;35:457–74.CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Cunci L, Vargas MM, Cunci R, Gomez-Moreno R, Perez I, Baerga-Ortiz A, et al. Real-time detection of telomerase activity in Cancer cells using a label-free electrochemical Impedimetric biosensing microchip. RSC Adv. 2014;4:52357–65.CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Califano J, Ahrendt SA, Meininger G, Westra WH, Koch WM, Sidransky D. Detection of telomerase activity in oral rinses from head and neck squamous cell carcinoma patients. Cancer Res. 1996;56:5720–2.PubMedGoogle Scholar
  178. 178.
    Hess JL, Highsmith WE Jr. Telomerase detection in body fluids. Clin Chem. 2002;48:18–24.PubMedGoogle Scholar
  179. 179.
    Zuo X, Xia F, Patterson A, Soh HT, Xiao Y, Plaxco KW. Two-step, PCR-free telomerase detection by using exonuclease III-aided target recycling. Chembiochem. 2011;12:2745–7.CrossRefPubMedGoogle Scholar
  180. 180.
    Wang HB, Wu S, Chu X, Yu RQ. A sensitive fluorescence strategy for telomerase detection in cancer cells based on T7 exonuclease-assisted target recycling amplification. ChemCommun (Camb). 2012;48:5916–8.CrossRefGoogle Scholar
  181. 181.
    Liu X, Li W, Hou T, Dong S, Yu G, Li F. Homogeneous electrochemical strategy for human telomerase activity assay at single-cell level based on T7 exonuclease-aided target recycling amplification. Anal Chem. 2015;87:4030–6.CrossRefPubMedGoogle Scholar
  182. 182.
    Chaudhary AK, Pandya S, Mehrotra R, Bharti AC, Singh M, Singh M. Comparative study between the hybrid capture II test and PCR based assay for the detection of human papillomavirus DNA in oral submucous fibrosis and oral squamous cell carcinoma. Virol J. 2010;7:253.CrossRefPubMedPubMedCentralGoogle Scholar
  183. 183.
    Gichki AS, Buajeeb W, Doungudomdacha S, Khovidhunkit SO. Detection of human papillomavirus in normal oral cavity in a group of Pakistani subjects using real-time PCR. Asian Pac J Cancer Prev. 2012;13:2299–304.CrossRefPubMedGoogle Scholar
  184. 184.
    Tsiodras S, Georgoulakis J, Chranioti A, Voulgaris Z, Psyrri A, Tsivilika A, et al. Hybrid capture vs. PCR screening of cervical human papilloma virus infections. Cytological and histological associations in 1270 women. BMC Cancer. 2010;10:53.CrossRefPubMedPubMedCentralGoogle Scholar
  185. 185.
    Lin CY, Li L. Comparison of DNA testing strategies in monitoring human papillomavirus infection prevalence through simulation. BMC Infect Dis. 2016;16:642.CrossRefPubMedPubMedCentralGoogle Scholar
  186. 186.
    Geraets DT, Cuschieri K, de Koning MNC, van Doorn LJ, Snijders PJF, Meijer CJLM, et al. Clinical evaluation of a GP5+/6+-based Luminex assay having full high-risk human papillomavirus genotyping capability and an internal control. J Clin Microbiol. 2014;52:3996–4002.CrossRefPubMedPubMedCentralGoogle Scholar
  187. 187.
    David J. Beale, Oliver A. H. Jones, Avinash V. Karpe, Saravanan Dayalan, Ding Yuan Oh, Konstantinos A. Kouremenos, et al. A review of analytical techniques and their application in disease diagnosis in Breathomics and Salivaomics research. Int J Mol Sci 2017; 18: 24.Google Scholar
  188. 188.
    Ishikawa S, Sugimoto M, Kitabatake K, Sugano A, Nakamura M, Kaneko M, et al. Identification of salivary metabolomic biomarkers for oral cancer screening. Sci Rep. 2016;6:31520.CrossRefPubMedPubMedCentralGoogle Scholar
  189. 189.
    Ogawa T, Washio J, Takahashi T, Echigo S, Takahashi N. Glucose and glutamine metabolism in oral squamous cell carcinoma: insight from a quantitative metabolomic approach. Oral Surg Oral Med OralPathol Oral Radiol. 2014;118:218–25.CrossRefGoogle Scholar
  190. 190.
    Sandulache VC, Ow TJ, Pickering CR, Frederick MJ, Zhou G, Fokt I, et al. Glucose, not glutamine, is the dominant energy source required for proliferation and survival of head and neck squamous carcinoma cells. Cancer. 2011;117:2926–38.CrossRefPubMedPubMedCentralGoogle Scholar
  191. 191.
    Wang Q, Gao P, Wang X, Duan Y. Investigation and identification of potential biomarkers in human saliva for the early diagnosis of oral squamous cell carcinoma. ClinChim Acta. 2014;427:79–85.CrossRefGoogle Scholar
  192. 192.
    Wang Q, Gao P, Cheng F, Wang X, Duan Y. Measurement of salivary metabolite biomarkers for early monitoring of oral cancer with ultra performance liquid chromatography-mass spectrometry. Talanta. 2014;119:299–305.CrossRefPubMedGoogle Scholar
  193. 193.
    Chiang PK, Gordon RK, Tal J, Zeng GC, Doctor BP, Pardhasaradhi K, McCann PP. S-Adenosylmethionine and methylation. FASEB J. 1996;10:471–80.CrossRefPubMedGoogle Scholar
  194. 194.
    Iwata S, Sato Y, Asada M, Takagi M, Tsujimoto A, Inaba T, et al. Anti-tumor activity of antizyme which targets the ornithine decarboxylase (ODC) required for cell growth and transformation. Oncogene. 1999;18:165–72.CrossRefPubMedGoogle Scholar
  195. 195.
    Katakwar P, Metgud R, Naik S, Mittal R. Oxidative stress marker in oral cancer: a review. J Cancer Res Ther. 2016;12:438–46.CrossRefPubMedGoogle Scholar
  196. 196.
    Reznick AZ, Hershkovich O, Nagler RM. Saliva--a pivotal player in the pathogenesis of oropharyngeal cancer. Br J Cancer. 2004;91:111–8.CrossRefPubMedPubMedCentralGoogle Scholar
  197. 197.
    Shpitzer T, Hamzany Y, Bahar G, Feinmesser R, Savulescu D, Borovoi I, et al. Salivary analysis of oral cancer biomarkers. Br J Cancer. 2009;101:1194–8.CrossRefPubMedPubMedCentralGoogle Scholar
  198. 198.
    Khoubnasabjafari M, Ansarin K, Jouyban A. Salivary malondialdehyde as an oxidative stress biomarker in oral and systemic diseases. J Dent Res Dent Clin Dent Prospects. 2016 Spring;10:71–4.CrossRefPubMedPubMedCentralGoogle Scholar
  199. 199.
    Chole RH, Patil RN, Basak A, Palandurkar K, Bhowate R. Estimation of serum malondialdehyde in oral cancer and precancer and its association with healthy individuals, gender, alcohol, and tobaccoabuse. J Cancer Res Ther. 2010;6:487–91.CrossRefPubMedGoogle Scholar
  200. 200.
    Shetty SR, Babu S, Kumari S, Shetty P, Hegde S, Castelino R. Status of salivary lipid peroxidation in oral cancer and precancer. Indian J Med Paediatr Oncol. 2014;35:156–8.CrossRefPubMedPubMedCentralGoogle Scholar
  201. 201.
    Peluso I, Raguzzini A. Salivary and urinary Total antioxidant capacity as biomarkers of oxidative stress in humans. Patholog Res Int. 2016;2016:5480267.PubMedPubMedCentralGoogle Scholar
  202. 202.
    Kaur J, Politis C, Jacobs R. Salivary 8-hydroxy-2-deoxyguanosine, malondialdehyde, vitamin C, and vitamin E in oral pre-cancer and cancer: diagnostic value and free radical mechanism of action. Clin Oral Investig. 2016;20:315–9.CrossRefPubMedGoogle Scholar
  203. 203.
    Zhang Y, Sun J, Lin CC, Abemayor E, Wang MB, Wong DT. The emerging landscape of salivary diagnostics. Oral Health Dent Manag. 2014;13:200–10.PubMedGoogle Scholar
  204. 204.
    Mager DL, Haffajee AD, Devlin PM, Norris CM, Posner MR, Goodson JM. The salivary microbiota as a diagnostic indicator of oral cancer: a descriptive, non-randomized study of cancer-free and oral squamous cell carcinoma subjects. J Transl Med. 2005;3:27.CrossRefPubMedPubMedCentralGoogle Scholar
  205. 205.
    Pushalkar S, Mane SP, Ji X, Li Y, Evans C, Crasta OR, et al. Microbial diversity in saliva of oral squamous cell carcinoma. FEMS Immunol Med Microbiol. 2011;61:269–77.CrossRefPubMedPubMedCentralGoogle Scholar
  206. 206.
    Pushalkar S, Ji X, Li Y, Estilo C, Yegnanarayana R, Singh B, et al. Comparison of oral microbiota in tumor and non-tumor tissues of patients with oral squamous cell carcinoma. BMC Microbiol. 2012;12:144.CrossRefPubMedPubMedCentralGoogle Scholar
  207. 207.
    Guerrero-Preston R, Godoy-Vitorino F, Jedlicka A, Rodríguez-Hilario A, González H, Bondy J, et al. 16S rRNA amplicon sequencing identifies microbiota associated with oral cancer, human papilloma virus infection and surgical treatment. Oncotarget. 2016;7:51320–34.CrossRefPubMedPubMedCentralGoogle Scholar
  208. 208.
    Hu X, Zhang Q, Hua H, Chen F. Changes in the salivary microbiota of oral leukoplakia and oral cancer. Oral Oncol. 2016;56:e6–8.CrossRefPubMedGoogle Scholar
  209. 209.
    Schmidt BL, Kuczynski J, Bhattacharya A, Huey B, Corby PM, Queiroz EL, et al. Changes in abundance of oral microbiota associated with oral cancer. PLoS One. 2014;9:e98741.CrossRefPubMedPubMedCentralGoogle Scholar
  210. 210.
    Hooper SJ, Crean SJ, Fardy MJ, Lewis MA, Spratt DA, Wade WG, et al. A molecular analysis of the bacteria present within oral squamous cell carcinoma. J Med Microbiol. 2007;56:1651–9.CrossRefPubMedGoogle Scholar
  211. 211.
    Błoniarz J, Rahnama M, Zareba S. Influence of carcinogenesis in the oral cavity on the level of some bioelements in the saliva. Rocz PanstwZakl Hig. 2003;54:295–300.Google Scholar
  212. 212.
    Dziewulska A, Janiszewska-Olszowska J, Bachanek T, Grocholewicz K. Salivary mineral composition in patients with oral cancer. Magnes Res. 2013;26:120–4.PubMedGoogle Scholar
  213. 213.
    Fuchs PN, Rogić D, Vidović-Juras D, Susić M, Milenović A, Brailo V, et al. Salivary analytes in patients with oral squamous cell carcinoma. Coll Antropol. 2011;35:359–62.PubMedGoogle Scholar
  214. 214.
    Zhang S, Zhang X, Yin K, Li T, BaoY, Chen Z. Variation and significance of secretory immunoglobulin A, interleukin 6 and dendritic cells in oral cancer. Oncol Lett. 2017; 13:2297–2303.Google Scholar
  215. 215.
    Johansen FE, Braathen R, Brandtzaeg P. Role of J chain in secretory immunoglobulin formation. Scand J Immunol. 2000;52:240–8.CrossRefPubMedGoogle Scholar
  216. 216.
    Farhad Mollashahi L, Honarmand M, Nakhaee A, Mollashahi G. Salivary Sialic acid levels in smokeless tobacco users. Int J High Risk Behav Addict. 2016;5:e27969.CrossRefPubMedPubMedCentralGoogle Scholar
  217. 217.
    Kurtul N, Gökpınar E. Salivary lipid peroxidation and total sialic acid levels in smokers and smokeless tobacco users as Maraş powder. Mediat Inflamm 2012;2012:619293.Google Scholar
  218. 218.
    Vajaria BN, Patel KR, Begum R, Shah FD, Patel JB, Shukla SN, et al. Evaluation of serum and salivary total sialic acid and α-l-fucosidase in patients with oral precancerous conditions and oral cancer. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115:764–71.CrossRefPubMedGoogle Scholar
  219. 219.
    Chaudhari V, Pradeep GL, Prakash N, Mahajan AM. Estimation of salivary sialic acid in oral premalignancy and oral squamous cell carcinoma. Contemp Clin Dent. 2016;7:451–6.CrossRefPubMedPubMedCentralGoogle Scholar
  220. 220.
    Winck FV, Prado Ribeiro AC, Ramos Domingues R, Ling LY, Riaño-Pachón DM, Rivera C, et al. Insights into immune responses in oral cancer through proteomic analysis of saliva and salivary extracellular vesicles. Sci Rep. 2015;5:16305.CrossRefPubMedPubMedCentralGoogle Scholar
  221. 221.
    Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol. 2008;10:619–24.CrossRefPubMedGoogle Scholar
  222. 222.
    Palanisamy V, Sharma S, Deshpande A, Zhou H, Gimzewski J, Wong DT. Nanostructural and transcriptomic analyses of human saliva derived exosomes. PLoS One. 2010;5:e8577.CrossRefPubMedPubMedCentralGoogle Scholar
  223. 223.
    Sharma S, Rasool HI, Palanisamy V, Mathisen C, Schmidt M, Wong DT, et al. Structural- mechanical characterization of nanoparticles-Exosomes in human saliva, using correlative AFM, FESEM and force spectroscopy. ACS Nano. 2010;4:1921–6.CrossRefPubMedPubMedCentralGoogle Scholar
  224. 224.
    Sun Y, Xia Z, Shang Z, Sun K, Niu X, Qian L, et al. Facile preparation of salivary extracellular vesicles for cancer proteomics. Sci Rep. 2016;6:24669.CrossRefPubMedPubMedCentralGoogle Scholar
  225. 225.
    Chiang SH, Thomas GA, Liao W, Grogan T, Buck RL, Fuentes L, et al. RNAPro•SAL: a device for rapid and standardized collection of saliva RNA and proteins. Biotechniques. 2015; 58: 69–76.Google Scholar
  226. 226.
    Al-Tarawneh SK, Border MB, Dibble CF, Bencharit S. Defining salivary biomarkers using mass spectrometry-based proteomics: a systematic review. OMICS. 2011;15:353–61.CrossRefPubMedPubMedCentralGoogle Scholar
  227. 227.
    Stuani VT, Rubira CM, Sant'Ana AC, Santos PS. Salivary biomarkers as tools for oral squamous cell carcinoma diagnosis: a systematic review. Head Neck. 2017;39:797–811.CrossRefPubMedGoogle Scholar
  228. 228.
    Lu R, Zhang J, Sun W, Du G, Zhou G. Inflammation-related cytokines in oral lichen planus: an overview. J Oral Pathol Med. 2015;44:1–14.CrossRefPubMedGoogle Scholar
  229. 229.
    Lisa Cheng YS, Jordan L, Gorugantula LM, Schneiderman E, Chen HS, Rees T. Salivary interleukin-6 and -8 in patients with oral cancer and patients with chronic oral inflammatory diseases. J Periodontol. 2014;85:956–65.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Oral Medicine and RadiologyMNR Dental College and HospitalSangareddyIndia
  2. 2.Center for Oral/Head and Neck Oncology ResearchSchool of Dentistry, University of California Los AngelesLos AngelesUSA
  3. 3.Jonsson Comprehensive Cancer CenterUniversity of California Los AngelesLos AngelesUSA
  4. 4.Head and Neck Surgery/OtolaryngologyDavid Geffen School of Medicine, University of California Los AngelesLos AngelesUSA
  5. 5.School of Engineering and Applied ScienceUniversity of California Los AngelesLos AngelesUSA

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