J Korean Assoc Oral Maxillofac Surg.  2020 Oct;46(5):301-312. 10.5125/jkaoms.2020.46.5.301.

Salivary biomarkers in oral squamous cell carcinoma

• Nguyen TTH
• Sodnom-Ish B
• Choi SW
• Jung HI
• Cho J
• Hwang I
• Kim SM

• KMID: 2508254
• DOI: http://doi.org/10.5125/jkaoms.2020.46.5.301

Abstract

In disease diagnostics and health surveillance, the use of saliva has potential because its collection is convenient and noninvasive. Over the past two decades, the development of salivary utilization for the early detection of cancer, especially oral cavity and oropharynx cancer has gained the interest of the researcher and clinician. Until recently, the oral cavity and oropharynx cancers are still having a five-year survival rate of 62%, one of the lowest in all major human cancers. More than 90% of oral cancers are oral squamous cell carcinoma (OSCC). Despite the ease of accessing the oral cavity in clinical examination, most OSCC lesions are not diagnosed in the early stage, which is suggested to be the main cause of the low survival rate. Many studies have been performed and reported more than 100 potential saliva biomarkers for OSCC. However, there are still obstacles in figuring out the reliable OSCC salivary biomarkers and the clinical application of the early diagnosis protocol. The current review article discusses the emerging issues and is hoped to raise awareness of this topic in both researchers and clinicians. We also suggested the potential salivary biomarkers that are reliable, specific, and sensitive for the early detection of OSCC.

Keyword

Squamous cell carcinoma of head and neck; Mouth neoplasm; Saliva; Biomarkers

Figure

• 

  Fig. 1 Classification of biomarkers. Adapted from the article of Mishra and Verma 1 (Cancers [Basel] 2010;2:190-208) in accordance with the Creative Commons Attribution 3.0 Unported (CC BY 3.0) license.

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  Fig. 2 Variety of biomarkers found in saliva.

Reference

References

1. Mishra A, Verma M. 2010; Cancer biomarkers: are we ready for the prime time? Cancers (Basel). 2:190–208. https://doi.org/10.3390/cancers2010190 . DOI: 10.3390/cancers2010190. PMID: 24281040. PMCID: PMC3827599.

2. Shield KD, Ferlay J, Jemal A, Sankaranarayanan R, Chaturvedi AK, Bray F, et al. 2017; The global incidence of lip, oral cavity, and pharyngeal cancers by subsite in 2012. CA Cancer J Clin. 67:51–64. https://doi.org/10.3322/caac.21384 . DOI: 10.3322/caac.21384. PMID: 28076666.

3. Conway DI, Purkayastha M, Chestnutt IG. 2018; The changing epidemiology of oral cancer: definitions, trends, and risk factors. Br Dent J. 225:867–73. https://doi.org/10.1038/sj.bdj.2018.922 . DOI: 10.1038/sj.bdj.2018.922. PMID: 30412558.

4. Patel RS, Clark JR, Dirven R, Wyten R, Gao K, O'Brien CJ. 2009; Prognostic factors in the surgical treatment of patients with oral carcinoma. ANZ J Surg. 79:19–22. https://doi.org/10.1111/j.1445-2197.2008.04791.x . DOI: 10.1111/j.1445-2197.2008.04791.x. PMID: 19183373.

5. Gupta N, Gupta R, Acharya AK, Patthi B, Goud V, Reddy S, et al. 2016; Changing Trends in oral cancer - a global scenario. Nepal J Epidemiol. 6:613–9. https://doi.org/10.3126/nje.v6i4.17255 . DOI: 10.3126/nje.v6i4.17255. PMID: 28804673. PMCID: PMC5506386.

6. Johnson NW, Jayasekara P, Amarasinghe AA. 2011; Squamous cell carcinoma and precursor lesions of the oral cavity: epidemiology and aetiology. Periodontol 2000. 57:19–37. https://doi.org/10.1111/j.1600-0757.2011.00401.x . DOI: 10.1111/j.1600-0757.2011.00401.x. PMID: 21781177.

7. Ilbawi AM, Anderson BO. 2015; Cancer in global health: how do prevention and early detection strategies relate? Sci Transl Med. 7:278. https://doi.org/10.1126/scitranslmed.3008853 . DOI: 10.1126/scitranslmed.3008853. PMID: 25761886.

8. Lousada-Fernandez F, Rapado-Gonzalez O, Lopez-Cedrun JL, Lopez-Lopez R, Muinelo-Romay L, Suarez-Cunqueiro MM. 2018; Liquid biopsy in oral cancer. Int J Mol Sci. 19:1704. https://doi.org/10.3390/ijms19061704 . DOI: 10.3390/ijms19061704. PMID: 29890622. PMCID: PMC6032225.

9. Cheng YS, Rees T, Wright J. 2014; A review of research on salivary biomarkers for oral cancer detection. Clin Transl Med. 3:3. https://doi.org/10.1186/2001-1326-3-3 . DOI: 10.1186/2001-1326-3-3. PMID: 24564868. PMCID: PMC3945802.

10. Thomadaki K, Helmerhorst EJ, Tian N, Sun X, Siqueira WL, Walt DR, et al. 2011; Whole-saliva proteolysis and its impact on salivary diagnostics. J Dent Res. 90:1325–30. https://doi.org/10.1177/0022034511420721 . DOI: 10.1177/0022034511420721. PMID: 21917601. PMCID: PMC3188460.

11. Arglebe C. 1981; Biochemistry of human saliva. Adv Otorhinolaryngol. 26:97–234. https://doi.org/10.1159/000395291 . DOI: 10.1159/000395291. PMID: 7020374.

12. Kaczor-Urbanowicz KE, Martin Carreras-Presas C, Aro K, Tu M, Garcia-Godoy F, Wong DT. 2017; Saliva diagnostics - current views and directions. Exp Biol Med (Maywood). 245:459–72. https://doi.org/10.1177/1535370216681550 . DOI: 10.1177/1535370216681550. PMID: 27903834. PMCID: PMC5367650.

13. Hu S, Loo JA, Wong DT. 2007; Human saliva proteome analysis and disease biomarker discovery. Expert Rev Proteomics. 4:531–8. https://doi.org/10.1586/14789450.4.4.531 . DOI: 10.1586/14789450.4.4.531. PMID: 17705710.

14. Wong DT. 2012; Salivaomics. J Am Dent Assoc. 143(10 Suppl):19S–24S. https://doi.org/10.14219/jada.archive.2012.0339 . DOI: 10.14219/jada.archive.2012.0339. PMID: 23034834.

15. Tachibana M, Tonomoto Y, Hyakudomi R, Hyakudomi M, Hattori S, Ueda S, et al. 2007; Expression and prognostic significance of EFNB2 and EphB4 genes in patients with oesophageal squamous cell carcinoma. Dig Liver Dis. 39:725–32. https://doi.org/10.1016/j.dld.2007.05.013 . DOI: 10.1016/j.dld.2007.05.013. PMID: 17611172.

16. Shpitzer T, Hamzany Y, Bahar G, Feinmesser R, Savulescu D, Borovoi I, et al. 2009; Salivary analysis of oral cancer biomarkers. Br J Cancer. 101:1194–8. https://doi.org/10.1038/sj.bjc.6605290 . DOI: 10.1038/sj.bjc.6605290. PMID: 19789535. PMCID: PMC2768098.

17. Rajkumar K, Ramesh Kumar A, Ramyamalini V, Nandhini G, Dinesh Kumar T, Ashwini BK, et al. 2010; Estimation of serological and salivary biomarkers in patients vith oral squamous cell carcinoma, premalignant lesions & conditions. SRM J Res Dent Sci. 1:14–9.

18. St John MA, Li Y, Zhou X, Denny P, Ho CM, Montemagno C, et al. 2004; Interleukin 6 and interleukin 8 as potential biomarkers for oral cavity and oropharyngeal squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 130:929–35. https://doi.org/10.1001/archotol.130.8.929 . DOI: 10.1001/archotol.130.8.929. PMID: 15313862.

19. Arellano-Garcia ME, Hu S, Wang J, Henson B, Zhou H, Chia D, et al. 2008; Multiplexed immunobead-based assay for detection of oral cancer protein biomarkers in saliva. Oral Dis. 14:705–12. https://doi.org/10.1111/j.1601-0825.2008.01488.x . DOI: 10.1111/j.1601-0825.2008.01488.x. PMID: 19193200. PMCID: PMC2675698.

20. Khurshid Z, Zafar MS, Khan RS, Najeeb S, Slowey PD, Rehman IU. 2018; Role of salivary biomarkers in oral cancer detection. Adv Clin Chem. 86:23–70. https://doi.org/10.1016/bs.acc.2018.05.002 . DOI: 10.1016/bs.acc.2018.05.002. PMID: 30144841.

21. de Jong EP, Xie H, Onsongo G, Stone MD, Chen XB, Kooren JA, et al. 2010; Quantitative proteomics reveals myosin and actin as promising saliva biomarkers for distinguishing pre-malignant and malignant oral lesions. PLoS One. 5:e11148. https://doi.org/10.1371/journal.pone.0011148 . DOI: 10.1371/journal.pone.0011148. PMID: 20567502. PMCID: PMC2887353.

22. Wang Q, Gao P, Wang X, Duan Y. 2014; Investigation and identification of potential biomarkers in human saliva for the early diagnosis of oral squamous cell carcinoma. Clin Chim Acta. 427:79–85. https://doi.org/10.1016/j.cca.2013.10.004 . DOI: 10.1016/j.cca.2013.10.004. PMID: 24144867.

23. Camisasca DR, da Rós Gonçalves L, Soares MR, Sandim V, Nogueira FC, Garcia CH, et al. 2017; A proteomic approach to compare saliva from individuals with and without oral leukoplakia. J Proteomics. 151:43–52. https://doi.org/10.1016/j.jprot.2016.07.029 . DOI: 10.1016/j.jprot.2016.07.029. PMID: 27478070.

24. Flores IL, Santos-Silva AR, Coletta RD, Leme AF, Lopes MA. 2016; Low expression of angiotensinogen and dipeptidyl peptidase 1 in saliva of patients with proliferative verrucous leukoplakia. World J Clin Cases. 4:356–63. https://doi.org/10.12998/wjcc.v4.i11.356 . DOI: 10.12998/wjcc.v4.i11.356. PMID: 27900324. PMCID: PMC5112355.

25. Hu S, Arellano M, Boontheung P, Wang J, Zhou H, Jiang J, et al. 2008; Salivary proteomics for oral cancer biomarker discovery. Clin Cancer Res. 14:6246–52. https://doi.org/10.1158/1078-0432.CCR-07-5037 . DOI: 10.1158/1078-0432.CCR-07-5037. PMID: 18829504. PMCID: PMC2877125.

26. Almadori G, Bussu F, Galli J, Limongelli A, Persichilli S, Zappacosta B, et al. 2007; Salivary glutathione and uric acid levels in patients with head and neck squamous cell carcinoma. Head Neck. 29:648–54. https://doi.org/10.1002/hed.20579 . DOI: 10.1002/hed.20579. PMID: 17274058.

27. Jou YJ, Lin CD, Lai CH, Chen CH, Kao JY, Chen SY, et al. 2010; Proteomic identification of salivary transferrin as a biomarker for early detection of oral cancer. Anal Chim Acta. 681:41–8. https://doi.org/10.1016/j.aca.2010.09.030 . DOI: 10.1016/j.aca.2010.09.030. PMID: 21035601.

28. Katakura A, Kamiyama I, Takano N, Shibahara T, Muramatsu T, Ishihara K, et al. 2007; Comparison of salivary cytokine levels in oral cancer patients and healthy subjects. Bull Tokyo Dent Coll. 48:199–203. https://doi.org/10.2209/tdcpublication.48.199 . DOI: 10.2209/tdcpublication.48.199. PMID: 18360107.

29. Duffy SA, Taylor JM, Terrell JE, Islam M, Li Y, Fowler KE, et al. 2008; Interleukin-6 predicts recurrence and survival among head and neck cancer patients. Cancer. 113:750–7. https://doi.org/10.1002/cncr.23615 . DOI: 10.1002/cncr.23615. PMID: 18536030.

30. Zhong LP, Chen GF, Xu ZF, Zhang X, Ping FY, Zhao SF. 2005; Detection of telomerase activity in saliva from oral squamous cell carcinoma patients. Int J Oral Maxillofac Surg. 34:566–70. https://doi.org/10.1016/j.ijom.2004.10.007 . DOI: 10.1016/j.ijom.2004.10.007. PMID: 16053879.

31. Krishna Prasad RB, Sharma A, Babu HM. 2013; An insight into salivary markers in oral cancer. Dent Res J (Isfahan). 10:287–95.

32. Franzmann EJ, Reategui EP, Pedroso F, Pernas FG, Karakullukcu BM, Carraway KL, et al. 2007; Soluble CD44 is a potential marker for the early detection of head and neck cancer. Cancer Epidemiol Biomarkers Prev. 16:1348–55. https://doi.org/10.1158/1055-9965.EPI-06-0011 . DOI: 10.1158/1055-9965.EPI-06-0011. PMID: 17627000.

33. Kumar M, Srivastava G, Kaur J, Assi J, Alyass A, Leong I, et al. 2015; Prognostic significance of cytoplasmic S100A2 overexpression in oral cancer patients. J Transl Med. 13:8. https://doi.org/10.1186/s12967-014-0369-9 . DOI: 10.1186/s12967-014-0369-9. PMID: 25591983. PMCID: PMC4324434.

34. Righini CA, de Fraipont F, Timsit JF, Faure C, Brambilla E, Reyt E, et al. 2007; Tumor-specific methylation in saliva: a promising biomarker for early detection of head and neck cancer recurrence. Clin Cancer Res. 13:1179–85. https://doi.org/10.1158/1078-0432.CCR-06-2027 . DOI: 10.1158/1078-0432.CCR-06-2027. PMID: 17317827.

35. Reddy I, Sherlin HJ, Ramani P, Premkumar P, Natesan A, Chandrasekar T. 2012; Amino acid profile of saliva from patients with oral squamous cell carcinoma using high performance liquid chromatography. J Oral Sci. 54:279–83. https://doi.org/10.2334/josnusd.54.279 . DOI: 10.2334/josnusd.54.279. PMID: 23047040.

36. Al Kawas S, Rahim ZH, Ferguson DB. 2012; Potential uses of human salivary protein and peptide analysis in the diagnosis of disease. Arch Oral Biol. 57:1–9. https://doi.org/10.1016/j.archoralbio.2011.06.013 . DOI: 10.1016/j.archoralbio.2011.06.013. PMID: 21774913.

37. Li Y, St John MA, Zhou X, Kim Y, Sinha U, Jordan RC, et al. 2004; Salivary transcriptome diagnostics for oral cancer detection. Clin Cancer Res. 10:8442–50. https://doi.org/10.1158/1078-0432.CCR-04-1167 . DOI: 10.1158/1078-0432.CCR-04-1167. PMID: 15623624.

38. Elashoff D, Zhou H, Reiss J, Wang J, Xiao H, Henson B, et al. 2012; Prevalidation of salivary biomarkers for oral cancer detection. Cancer Epidemiol Biomarkers Prev. 2:664–72. https://doi.org/10.1158/1055-9965.EPI-11-1093 . DOI: 10.1158/1055-9965.EPI-11-1093. PMID: 22301830. PMCID: PMC3319329.

39. Tang H, Wu Z, Zhang J, Su B. 2013; Salivary lncRNA as a potential marker for oral squamous cell carcinoma diagnosis. Mol Med Rep. 7:761–6. https://doi.org/10.3892/mmr.2012.1254 . DOI: 10.3892/mmr.2012.1254. PMID: 23292713.

40. Liu CJ, Lin SC, Yang CC, Cheng HW, Chang KW. 2012; Exploiting salivary miR-31 as a clinical biomarker of oral squamous cell carcinoma. Head Neck. 34:219–24. https://doi.org/10.1002/hed.21713 . DOI: 10.1002/hed.21713. PMID: 22083872.

41. Park NJ, Zhou H, Elashoff D, Henson BS, Kastratovic DA, Abemayor E, et al. 2009; Salivary microRNA: discovery, characterization, and clinical utility for oral cancer detection. Clin Cancer Res. 15:5473–7. https://doi.org/10.1158/1078-0432.CCR-09-0736 . DOI: 10.1158/1078-0432.CCR-09-0736. PMID: 19706812. PMCID: PMC2752355.

42. Wei J, Xie G, Zhou Z, Shi P, Qiu Y, Zheng X, et al. 2011; Salivary metabolite signatures of oral cancer and leukoplakia. Int J Cancer. 129:2207–17. https://doi.org/10.1002/ijc.25881 . DOI: 10.1002/ijc.25881. PMID: 21190195.

43. Sugimoto M, Wong DT, Hirayama A, Soga T, Tomita M. 2010; Capillary electrophoresis mass spectrometry-based saliva metabolomics identified oral, breast and pancreatic cancer-specific profiles. Metabolomics. 6:78–95. https://doi.org/10.1007/s11306-009-0178-y . DOI: 10.1007/s11306-009-0178-y. PMID: 20300169. PMCID: PMC2818837.

44. Ishikawa S, Sugimoto M, Kitabatake K, Sugano A, Nakamura M, Kaneko M, et al. 2016; Identification of salivary metabolomic biomarkers for oral cancer screening. Sci Rep. 6:31520. https://doi.org/10.1038/srep31520 . DOI: 10.1038/srep31520. PMID: 27539254. PMCID: PMC4990923.

45. Feng Y, Li Q, Chen J, Yi P, Xu X, Fan Y, et al. 2019; Salivary protease spectrum biomarkers of oral cancer. Int J Oral Sci. 11:7. https://doi.org/10.1038/s41368-018-0032-z . DOI: 10.1038/s41368-018-0032-z. PMID: 30602733. PMCID: PMC6315043.

46. Peng M, Chen C, Hulbert A, Brock MV, Yu F. 2017; Non-blood circulating tumor DNA detection in cancer. Oncotarget. 8:69162–73. https://doi.org/10.18632/oncotarget.19942 . DOI: 10.18632/oncotarget.19942. PMID: 28978187. PMCID: PMC5620327.

47. Zhang CZ, Cheng XQ, Li JY, Zhang P, Yi P, Xu X, et al. 2016; Saliva in the diagnosis of diseases. Int J Oral Sci. 8:133–7. https://doi.org/10.1038/ijos.2016.38 . DOI: 10.1038/ijos.2016.38. PMID: 27585820. PMCID: PMC5113094.

48. Gröbe A, Blessmann M, Hanken H, Friedrich RE, Schön G, Wikner J, et al. 2014; Prognostic relevance of circulating tumor cells in blood and disseminated tumor cells in bone marrow of patients with squamous cell carcinoma of the oral cavity. Clin Cancer Res. 20:425–33. https://doi.org/10.1158/1078-0432.CCR-13-1101 . DOI: 10.1158/1078-0432.CCR-13-1101. PMID: 24218516.

49. Bhattarai KR, Kim HR, Chae HJ. 2018; Compliance with saliva collection protocol in healthy volunteers: strategies for managing risk and errors. Int J Med Sci. 15:823–31. https://doi.org/10.7150/ijms.25146 . DOI: 10.7150/ijms.25146. PMID: 30008593. PMCID: PMC6036086.

50. Golatowski C, Salazar MG, Dhople VM, Hammer E, Kocher T, Jehmlich N, et al. 2013; Comparative evaluation of saliva collection methods for proteome analysis. Clin Chim Acta. 419:42–6. https://doi.org/10.1016/j.cca.2013.01.013 . DOI: 10.1016/j.cca.2013.01.013. PMID: 23384500.

51. Navazesh M. 1993; Methods for collecting saliva. Ann N Y Acad Sci. 694:72–7. https://doi.org/10.1111/j.1749-6632.1993.tb18343.x . DOI: 10.1111/j.1749-6632.1993.tb18343.x. PMID: 8215087.

52. Yoshizawa JM, Schafer CA, Schafer JJ, Farrell JJ, Paster BJ, Wong DT. 2013; Salivary biomarkers: toward future clinical and diagnostic utilities. Clin Microbiol Rev. 26:781–91. https://doi.org/10.1128/CMR.00021-13 . DOI: 10.1128/CMR.00021-13. PMID: 24092855. PMCID: PMC3811231.

53. Nassar M, Hiraishi N, Islam S, Otsuki M, Tagami J. 2014; Age-related changes in salivary biomarkers. J Dent Sci. 9:85–90. https://doi.org/10.1016/j.jds.2013.11.002 . DOI: 10.1016/j.jds.2013.11.002.

54. Cabras T, Pisano E, Boi R, Olianas A, Manconi B, Inzitari R, et al. 2009; Age-dependent modifications of the human salivary secretory protein complex. J Proteome Res. 8:4126–34. https://doi.org/10.1021/pr900212u . DOI: 10.1021/pr900212u. PMID: 19591489.

55. Fenoll-Palomares C, Muñoz Montagud JV, Sanchiz V, Herreros B, Hernández V, Mínguez M, et al. 2004; Unstimulated salivary flow rate, pH and buffer capacity of saliva in healthy volunteers. Rev Esp Enferm Dig. 96:773–83. https://doi.org/10.4321/s1130-01082004001100005 . DOI: 10.4321/S1130-01082004001100005. PMID: 15584851.

56. Chiappin S, Antonelli G, Gatti R, De Palo EF. 2007; Saliva specimen: a new laboratory tool for diagnostic and basic investigation. Clin Chim Acta. 383:30–40. https://doi.org/10.1016/j.cca.2007.04.011 . DOI: 10.1016/j.cca.2007.04.011. PMID: 17512510.

57. Henson BS, Wong DT. 2010; Collection, storage, and processing of saliva samples for downstream molecular applications. Methods Mol Biol. 666:21–30. https://doi.org/10.1007/978-1-60761-820-1_2 . DOI: 10.1007/978-1-60761-820-1_2. PMID: 20717775.

58. Shirtcliff EA, Granger DA, Schwartz E, Curran MJ. 2001; Use of salivary biomarkers in biobehavioral research: cotton-based sample collection methods can interfere with salivary immunoassay results. Psychoneuroendocrinology. 26:165–73. https://doi.org/10.1016/s0306-4530(00)00042-1 . DOI: 10.1016/S0306-4530(00)00042-1.

59. Williamson S, Munro C, Pickler R, Grap MJ, Elswick RK Jr Jr. 2012; Comparison of biomarkers in blood and saliva in healthy adults. Nurs Res Pract. 2012:246178. https://doi.org/10.1155/2012/246178 . DOI: 10.1155/2012/246178. PMID: 22619709. PMCID: PMC3350846.

60. Ngamchuea K, Batchelor-McAuley C, Cowen PJ, Williams C, Gonçalves LM, Compton RG. 2016; Can saliva testing replace blood measurements for health monitoring? Insights from a correlation study of salivary and whole blood glutathione in humans. Analyst. 14:4707–12. https://doi.org/10.1039/c6an01139j . DOI: 10.1039/C6AN01139J. PMID: 27278110.

61. Sharma M, Sharma E, Prabhu V, Pai VR, D'souza JM, Harish S, et al. 2020; Salivary L-fucose as a biomarker for oral potentially malignant disorders and oral cancer. J Cancer Res Ther. 16:546–50. https://doi.org/10.4103/jcrt.JCRT_552_17 . DOI: 10.4103/jcrt.JCRT_552_17. PMID: 32719265.

62. Singh P, Barpande SR, Bhavthankar JD, Mandale MS, Bhagwat AU. 2017; Serum Cyfra 21-1 levels in oral squamous cell carcinoma patients and its clinicopathologic correlation. Indian J Dent Res. 28:162–8. https://doi.org/10.4103/0970-9290.207789 . DOI: 10.4103/0970-9290.207789. PMID: 28611326.

63. Aziz NZ, Arathi K, Prasad BG, Desai D, Shetty SJ, Shahid M. 2018; Evaluation of magnesium levels in blood and saliva of oral squamous cell carcinoma and potentially malignant disorders by xylidyl blue method. J Oral Maxillofac Pathol. 22:147. https://doi.org/10.4103/jomfp.JOMFP_34_17 .

64. Metgud R, Patel S. 2014; Serum and salivary levels of albumin as diagnostic tools for oral pre-malignancy and oral malignancy. Biotech Histochem. 89:8–13. https://doi.org/10.3109/10520295.2013.793394 . DOI: 10.3109/10520295.2013.793394. PMID: 23738795.

65. Ai J, Smith B, Wong DT. 2010; Saliva ontology: an ontology-based framework for a Salivaomics knowledge base. BMC Bioinformatics. 11:302. https://doi.org/10.1186/1471-2105-11-302 . DOI: 10.1186/1471-2105-11-302. PMID: 20525291. PMCID: PMC2898059.

66. Wu CC, Chu HW, Hsu CW, Chang KP, Liu HP. 2015; Saliva proteome profiling reveals potential salivary biomarkers for detection of oral cavity squamous cell carcinoma. Proteomics. 15:3394–404. https://doi.org/10.1002/pmic.201500157 . DOI: 10.1002/pmic.201500157. PMID: 26205615.

67. Flannery CR. 2006; MMPs and ADAMTSs: functional studies. Front Biosci. 11:544–69. https://doi.org/10.2741/1818 . DOI: 10.2741/1818. PMID: 16146752.

68. Kim JM, Kang SW, Shin SM, Su Kim D, Choi KK, Kim EC, et al. 2014; Inhibition of matrix metalloproteinases expression in human dental pulp cells by all-trans retinoic acid. Int J Oral Sci. 6:150–3. https://doi.org/10.1038/ijos.2013.63 . DOI: 10.1038/ijos.2013.63. PMID: 24008270. PMCID: PMC4170145.

69. Edwards DR, Handsley MM, Pennington CJ. 2008; The ADAM metalloproteinases. Mol Aspects Med. 29:258–89. https://doi.org/10.1016/j.mam.2008.08.001 . DOI: 10.1016/j.mam.2008.08.001. PMID: 18762209. PMCID: PMC7112278.

70. Chu HW, Chang KP, Hsu CW, Chang IY, Liu HP, Chen YT, et al. 2019; Identification of salivary biomarkers for oral cancer detection with untargeted and targeted quantitative proteomics approaches. Mol Cell Proteomics. 18:1796–806. https://doi.org/10.1074/mcp.RA119.001530 . DOI: 10.1074/mcp.RA119.001530. PMID: 31253657. PMCID: PMC6731081.