Recent advancements in mass spectrometric proteomics provide a promising result in utilizing saliva to explore biomarkers for diagnostic purposes. However, the issues of specificity or redundancy of disease-associated salivary biomarkers have not been described. This systematic review was therefore aimed to define and summarize disease-related salivary biomarkers identified by mass spectrometry proteomics. Peer-reviewed articles published through July 2009 within three databases were reviewed. Out of 243 articles, 21 studies were selected in this systematic review with conditions including Sjögren's syndrome, squamous cell carcinoma, dental caries, diabetes, breast cancer, periodontitis, gastric cancer, systemic sclerosis, oral lichen planus, bleeding oral cavity, and graft-versus-host disease. The sample size ranged from 3–41 in both diseased and control subjects, with no consensus on sample collection protocol. One hundred eighty biomarkers were identified in total; 87 upregulated, 63 downregulated, and 30 varying based on disease. Except for Sjögren's syndrome, the majority of studies with the same disease produce inconsistent biomarkers. Larger sample size and standardization of sample collection/treatment protocol may improve future studies.
Get full access to this article
View all access options for this article.
References
1.
Al-TarawnehS.K., BencharitS.2009. Applications of surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry in defining salivary proteomic profiles. Open Dent J, 3:74–79.
2.
AtiomoW., KhalidS., ParameshweranS., HoudaM., LayfieldR.2009. Proteomic biomarkers for the diagnosis and risk stratification of polycystic ovary syndrome: a systematic review. BJOG, 116:137–143.
3.
BaldiniC., GiustiL., BazzichiL., CiregiaF., GiannacciniG., GiacomelliC.et al.2008a. Association of psoriasin (S100A7) with clinical manifestations of systemic sclerosis: is its presence in whole saliva a potential predictor of pulmonary involvement?J Rheumatol, 35:1820–1824.
4.
BaldiniC., GiustiL., BazzichiL., LucacchiniA., BombardieriS.2008b. Proteomic analysis of the saliva: a clue for understanding primary from secondary Sjögren's syndrome?Autoimmun Rev, 7:185–191.
5.
BiglerL.R., StreckfusC.F., CopelandL., BurnsR., DaiX., KuhnM.et al.2002. The potential use of saliva to detect recurrence of disease in women with breast carcinoma. J Oral Pathol Med, 31:421–431.
6.
BrinkmanB.M., WongD.T.2006. Disease mechanism and biomarkers of oral squamous cell carcinoma. Curr Opin Oncol, 18:228–233.
7.
BrooksM.N., WangJ., LiY., ZhangR., ElashoffD., WongD.T.2008. Salivary protein factors are elevated in breast cancer patients. Mol Med Report, 1:375–378.
8.
CaporossiL., SantoroA., PapaleoB.2010. Saliva as an analytical matrix: state of the art and application for biomonitoring. Biomarkers, 15:475–487.
9.
CarpenterG.H., ProctorG.B., PankhurstC.L., O'DonohueJ., ScottD., amd HunnableM.P.2000. Sialochemical markers of salivary gland involvement with Sjögren's syndrome secondary to rheumatoid arthritis and primary biliary cirrhosis. J Oral Pathol Med, 29:452–459.
10.
DoddsM.W., YehC.K., JohnsonD.A.2000. Salivary alterations in type 2 (non-insulin-dependent) diabetes mellitus and hypertension. Community Dent Oral Epidemiol, 28:373–381.
11.
DowlingP., WormaldR., MeleadyP., HenryM., CurranA., ClynesM.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. J Proteomics, 71:168–175.
12.
FleissigY., DeutschO., ReichenbergE., RedlichM., ZaksB., PalmonA.et al.2009. Different proteomic protein patterns in saliva of Sjögren's syndrome patients. Oral Dis, 15:61–68.
13.
GiustiL., BaldiniC., BazzichiL., CiregiaF., TonazziniI., MasciaG.et al.2007a. Proteome analysis of whole saliva: a new tool for rheumatic diseases—the example of Sjögren's syndrome. Proteomics, 7:1634–1643.
14.
GiustiL., BazzichiL., BaldiniC., CiregiaF., MasciaG., GiannacciniG.et al.2007b. Specific proteins identified in whole saliva from patients with diffuse systemic sclerosis. J Rheumatol, 34:2063–2069.
15.
GoodD.M., ThongboonkerdV., NovakJ., BascandsJ.L., SchanstraJ.P., CoonJ.J.et al.2007. Body fluid proteomics for biomarker discovery: lessons from the past hold the key to success in the future. J Proteome Res, 6:4549–4555.
16.
HelmerhorstE.J., OppenheimF.G.2007. Saliva: a dynamic proteome. J Dent Res, 86:680–693.
17.
HensonB.S., WongD.T.2010. Collection, storage, and processing of saliva samples for downstream molecular applications. Methods Mol Biol, 666:21–30.
18.
HirtzC., ChevalierF., SommererN., RaingeardI., BringerJ., RossignolM.et al.2006. Salivary protein profiling in type I diabetes using two-dimensional electrophoresis and mass spectrometry. Clin Proteomics, 2:117–128.
19.
HuS., LooJ.A., WongD.T.2007a. Human saliva proteome analysis and disease biomarker discovery. Expert Rev Proteomics, 4:531–538.
20.
HuS., WangJ., MeijerJ., IeongS., XieY., YuT.et al.2007b. Salivary proteomic and genomic biomarkers for primary Sjögren's syndrome. Arthritis Rheum, 56:3588–3600.
21.
HuS., YuT., XieY., YangY., LiY., ZhouX.et al.2007c. Discovery of oral fluid biomarkers for human oral cancer by mass spectrometry. Cancer Genomics Proteomics, 4:55–64.
22.
HuS., ArellanoM., BoontheungP., WangJ., ZhouH., JiangJ.et al.2008. Salivary proteomics for oral cancer biomarker discovery. Clin Cancer Res, 14:6246–6252.
23.
HuS., JiangJ., WongD.T.2010. Proteomic analysis of saliva: 2D gel electrophoresis, LC-MS/MS, and Western blotting. Methods Mol Biol, 666:31–41.
24.
HuangC.M.2004. Comparative proteomic analysis of human whole saliva. Arch Oral Biol, 49:951–962.
25.
ImanguliM.M., AtkinsonJ.C., HarveyK.E., HoehnG.T., RyuO.H., WuT.et al.2007. Changes in salivary proteome following allogeneic hematopoietic stem cell transplantation. Exp Hematol, 35:184–192.
26.
KomineK., KuroishiT., OzawaA., KomineY., MinamiT., ShimauchiH.et al.2007. Cleaved inflammatory lactoferrin peptides in parotid saliva of periodontitis patients. Mol Immunol, 44:1498–1508.
LiuZ., MaY., YangJ., QinH.2011. Upregulated and downregulated proteins in hepatocellular carcinoma: a systematic review of proteomic profiling studies. OMICS, 15:61–71.
29.
LooJ.A., YanW., RamachandranP., WongD.T.2010. Comparative human salivary and plasma proteomes. J Dent Res, 89:1016–1023.
30.
MessanaI., InzitariR., FanaliC., CabrasT., CastagnolaM.2008. Facts and artifacts in proteomics of body fluids. What proteomics of saliva is telling us? J Sep Sci, 31:1948–1963.
31.
OhshiroK., RosenthalD.I., KoomenJ.M., StreckfusC.F., ChambersM., KobayashiR.et al.2007. Pre-analytic saliva processing affect proteomic results and biomarker screening of head and neck squamous carcinoma. Int J Oncol, 30:743–749
32.
PelusoG., De SantisM., InzitariR., FanaliC., CabrasT., MessanaI.et al.2007. Proteomic study of salivary peptides and proteins in patients with Sjögren's syndrome before and after pilocarpine treatment. Arthritis Rheum, 56:2216–2222.
33.
PrezaD., ThiedeB., OlsenI., GrindeB.2009. The proteome of the human parotid gland secretion in elderly with and without root caries. Acta Odontol Scand, 67:161–169.
34.
RamachandranP., BoontheungP., XieY., SondejM., WongD.T., LooJ.A.2006. Identification of N-linked glycoproteins in human saliva by glycoprotein capture and mass spectrometry. J Proteome Res, 5:1493–1503.
35.
RaoP.V., ReddyA.P., LuX., DasariS., KrishnaprasadA., BiggsE.et al.2009. Proteomic identification of salivary biomarkers of type-2 diabetes. J Proteome Res, 8:239–245.
36.
RifaiN., GilletteM.A., CarrS.A.2006. Protein biomarker discovery and validation: the long and uncertain path to clinical utility. Nat Biotechnol, 24:971–983.
37.
RyuO.H., AtkinsonJ.C., HoehnG.T., IlleiG.G., HartT.C.2006. Identification of parotid salivary biomarkers in Sjögren's syndrome by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry and two-dimensional difference gel electrophoresis. Rheumatology, 45:1077–1086.
38.
SchipperR., LoofA., de GrootJ., HarthoornL., van HeerdeW., DransfieldE.2007. Salivary protein/peptide profiling with SELDI-TOF-MS. Ann N Y Acad Sci, 1098:498–503.
39.
StreckfusC., BiglerL.2005. The use of soluble, salivary c-erbB-2 for the detection and post-operative follow-up of breast cancer in women: the results of a five-year translational research study. Adv Dent Res, 18:17–24.
40.
StreckfusC.F., DubinskyW.P.2007. Proteomic analysis of saliva for cancer diagnosis. Expert Rev Proteomics, 4:329–332.
41.
StreckfusC.F., BiglerL.R., ZwickM.2006. The use of surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to detect putative breast cancer markers in saliva: a feasibility study. J Oral Pathol Med, 35:292–300.
42.
StreckfusC.F., Mayorga-WarkO., ArreolaD., EdwardsC., BiglerL., DubinskyW.P.2008. Breast cancer related proteins are present in saliva and are modulated secondary to ductal carcinoma in situ of the breast. Cancer Invest, 26:159–167.
43.
VitorinoR., de Morais GuedesS., FerreiraR., LoboM.J., DuarteJ., Ferrer-CorreiaA.J.et al.2006. Two-dimensional electrophoresis study of in vitro pellicle formation and dental caries susceptibility. Eur J Oral Sci, 114:147–153.
44.
WuY., ShuR., LuoL.J., GeL.H., XieY.F.2009a. Initial comparison of proteomic profiles of whole unstimulated saliva obtained from generalized aggressive periodontitis patients and healthy control subjects. J Periodontal Res., 44:636–644.
45.
WuZ.Z., WangJ.G., ZhangX.L.2009b. Diagnostic model of saliva protein finger print analysis of patients with gastric cancer. World J Gastroenterol, 15:865–870.
46.
YangL.L., LiuX.Q., LiuW., ChengB., LiM.T.2006. Comparative analysis of whole saliva proteomes for the screening of biomarkers for oral lichen planus. Inflamm Res, 55:405–407.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
