Oral Oncology 46 (2010) 226–231

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Oral Oncology
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Potential biomarkers in saliva for oral squamous cell carcinoma
Jia-Yo Wu a,b, Chen Yi a, Ho-Ren Chung a, Duen-Jeng Wang a, Wen-Chien Chang a,b, Sheng-Yang Lee a,
Che-Tung Lin a,b, Yueh-Chao Yang b,c, Wei-Chung Vivian Yang d,*
School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
Department of Dentistry, Taipei Medical University Hospital, Taipei, Taiwan
Department of Dentistry, Cathay General Hospital, Taipei, Taiwan
Graduate Institute of Biomedical Materials and Engineering, College of Oral Medicine, Taipei Medical University, No. 250 Wuxing Street, Taipei 110, Taiwan

a r t i c l e i n f o s u m m a r y

Article history: Sensitive and reliable early diagnostic markers for oral squamous cell carcinoma (OSCC) remain unavail-
Received 22 October 2009 able. Early identification of recurrence for OSCC is also a challenge. Unlike the other deep cancers, OSCC is
Received in revised form 8 January 2010 located in oral cavity. The DNA, RNA, and protein derived from the living cancer cells and inflammatory
Accepted 11 January 2010
cells then can be conveniently obtained from saliva. High-throughput genomic and proteomic approaches
Available online 6 February 2010
have been carried out to identify the potential biomarkers in body fluids such as saliva and blood for diag-
nosis and prognosis of OSCC. This article reviewed the recently identified biomarkers from saliva for
OSCC. In addition, the biomarkers which have been correlated with OSCC tumor malignancy by molecular
Body fluid
pathology analysis are also described. Finally, the potential biomarkers that have been demonstrated to
Diagnosis associate with the malignant OSCC may be used for salivary screening for high-risk patients are sug-
Genomics gested. This article may help to identify the potential biomarkers for screening and the molecular pathol-
Oral squamous cell carcinoma ogy analysis for high-risk patients of OSCC. Effective screening to identify high-risk patients can allow the
Prognosis clinician to provide the appropriate treatment without delay and to reduce the recurrence of OSCC.
Proteomics Ó 2010 Elsevier Ltd. All rights reserved.

Introduction high-risk tissues, but not in normal tissues; and (d) must be altered
in the early stages of cancer development. Unlike the other deep
Oral squamous cell carcinoma (OSCC) is a common human cancers, OSCC occurring in the oral cavity is much easier to be
malignant tumor with an increasing incidence. In Taiwan, oral can- monitored, specimens are easier to be collected for diagnosis,
cer has been one of the top ten causes of death from cancer since and the treatment is easier to be applied.
1991.1 The prevalence had a 5.3-fold increase for men and a 2-fold The modern high-throughput genomic and proteomic ap-
increase for women in two decades.2 In addition, the annual death proaches have been extensively used to observe the altered
toll for oral cancer in males has been increasing rapidly.3 Around expressions of gene and protein in a variety of cancers including
the world, the 5-year mortality rate of oral cancer is about 50%,4 OSCC. It may be helpful to facilitate the identification of potential
which has not changed significantly in recent 50 years despite of biomarkers for OSCC. To generate the genomic or proteomic
the advances in surgery, radiotherapy, and chemotherapy. This expression profiles, specimen collection is required. Tumor tissue
maybe due to most of the OSCC cases are diagnosed at a late stage and body fluid such as saliva or blood (serum and plasma) can
and no reliable early diagnostic marker is available. In addition, potentially carry whole cells as well as protein, DNA, and RNA spe-
OSCC has a very high recurrence rate, the early identification of cies that allow for detection of cellular alterations related to can-
recurrence or second primary tumors remains a challenge.5 Detec- cer.6,7 Compared to the tissue biopsy, body fluids have garnered
tion of OSCC is currently based on expert clinical examination and much more attention for biomarker identification. In addition,
histological analysis of suspicious areas, but it may be undetectable the body fluids such as blood remains the best choice for disease
in hidden sites. Therefore, sensitive and specific biomarkers for screening and diagnosis, because of the advantages in accessibility,
OSCC may be helpful to screening high-risk patients. low invasive procedure, low cost, and multiple sampling for mon-
The biomarkers for early cancer detection must meet the fol- itoring the disease development.8 Examples of using body fluids
lowing criteria: (a) the altered can be objectively measured; (b) for tumor detection include sputum for lung cancer diagnosis,9 ur-
must be measurable in small specimens; (c) must be altered in ine for urologic tumors,10 saliva for OSCC,11 breast fluid,12 as well
as serum or plasma for almost all types of cancer. Incorporation of
* Corresponding author. Tel.: +886 2 27361661x5208. genomic tools into oral cancer research is the focal point during
E-mail address: vyang@tmu.edu.tw (Wei-Chung Vivian Yang). the past years.13

1368-8375/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.

examples.f 18.24 In addition. Although h High performance liquid chromatography (HPLC). MRP14 dd 76 p53 antibodies dc 72. region gamma itoring the OSCC development. 18. For b Immunoradiometric assay. mitis in saliva com.85 the cancerous tissue were also described.87 sponse to events in oral cavity.5 tients with OSCC are listed in Table 1. in salivary proteomics for biomarker identification of OSCC. used for identifying the serum markers in blood sample. The potential biomarkers identified from saliva in pa. the levels of serum markers sometimes were not sensitive enough i PCR and ELISA. concluded that oral cancer subjects had elevated duced OSCC. saliva has the advantages of easily accessible in a Cyfra 21-1 db 18.80. melaninogenica and S.29 TNF- salivary DNA was advocated as an effective biomarker for the early a. inter- leukin 8 (IL-8). interleukin 1b (IL-1b.32. / Oral Oncology 46 (2010) 226–231 227 Up to date. which may contain reliable biomarkers for detecting OSCC include Molecule Saliva References blood and saliva. squamous cell carcinoma antigen (SCCAg) m Real-time quantitative polymerase chain reaction and RNA microarray. and IL-8) were significantly elevated in the whole d Immunoblot. but also serves as an amplifier of the signal relating to tumor cells. ronmental carcinogen such as tobacco or areca (betel) chewing in- tion.5 A mutated p53 gene in salivary for oral cancer diagnos.17 Immunoglobulin heavy chain constant de 77 proach using saliva to screen high-risk patients of OSCC and mon. By using the genomic approach for biomarker identifi- The tumor-specific DNA in saliva could be used as a biomarker cation of OSCC. Catalase dd 76 ers” from a plethora of biomarkers becomes an important issue. and proteins) and inhibitory substances and less com- Interleukin 1a (IL-1a) dc 17 plex than blood.28 IL-8. Mager et al.18 j DNA microarray. low background of normal material (cells.82.-Y. IL-6.14 Some OAZ dm 13 authors speculated that salivary gland could not only be viewed as S100P dl 87 SAT dm 13.17 The proteomic approach is also g Quantitative real time RT-PCR. some of the biomarkers were discov.21 Methylation array of In addition. were also widely identified through microarray technology.27 IL-6.19. k they might be still meaningful in the diagnosis of recurrence and Methylation-specific PCR. f Time-resolved fluoroimmunoassay (TRFIA). IL-1a. The aberrant expressions of CD44.34 and TNF-a35 were correlated to the envi- OSCC development. to be used for screening and early diagnosis of primary OSCC. since mRNA is the direct in both saliva and serum of patients with OSCC using proteomic precursor of proteins. RNA.73 proach to discover the potential biomarkers in blood and saliva for Profilin dd 76 OSCC. How to validate and distinguish the ‘‘true biomark. Proteomics* Genomics* ered with small sample size and some biomarkers that merely re- Albumin da 74 flect changes of biological variability may not be the ‘‘true Cancer antigen 125 (CA125) db 75 biomarkers”.30 and VEGF31 were found to be associated with the development detection of OSCC. e saliva of subjects with OSCC compared to patients with oral prema. CK 8. there have been hundreds of researches about OSCC Table 1 biomarkers identified in body fluids. prognosis.87 found in saliva is HER2/neu. carcinogen induced altered proteins described above were mainly .75. whether the biomarkers have Telomerase di di 83 been immunohistologically confirmed in the different stage of TNF-a dc 17.15 With * The analytical method using proteomic or genomic approach for identification the advances in mass spectrometry. l RT-PCR and RNA microarray. Endothelin-1 dg 78 Glutathione dh 79 DNR.75 non-invasive manner.26 tics was reported by Liao and coworkers. S100 calcium binding protein (S100P) were re- Salivary genomics ported by using both salivary transcriptomic and proteomic approaches. gingivalis.14–16 The first biomarker for cancer IL-8 dm 13. c Enzyme-linked immunosorbent assay (ELISA). This review may help Transferrin de 77 to improve the discovery of potential salivary biomarkers for early Transthyretin de 77 diagnosis and prognosis of OSCC. pro-angiogenic cytokines (TNF. lignant lesions and the control. The typical polymorphism and the environmental counts of C.20 After reviewing the published reports. and antibodies responsive to the gene aberrations such as anti-p53 antibodies were identified pared to OSCC-free subjects. Whether the biomarkers in saliva are presence or absence in S100 calcium binding protein de 77 blood were discussed. P.23 Microorganism infection may be involved in of OSCC.64 biomarkers of OSCC. In addition. It is also applicable and a non-invasive ap. IL-1b dm 13. Liquid chromatograph/mass spectrometer (LC/MS). a. cyfra 21-1 (CK19) and tissue polypeptide antigen (TPA. cific gene such as p16 promoter was found in serum25 and saliva. The effective diagnosis can lead a-Amylase da 86 b Fibrin de 77 to appropriate treatments and to prevent the recurrence of OSCC.13 The fallen cells in oral cavity allow saliva to be Interleukin 1b (IL-1b) dc 80 the first choice of screening and the identification for the potential Interleukin 6 (IL-6) dc 17. J. Wu et al. a Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS).33 VEGF.22. the fragment released from cytokeratin.84 Tissue polypeptide antigen (TPA) dc. the pro-inflammatory. P53.87 a sensor that detects a change in the plasma composition.25. We therefore collected the Mac-2 binding protein (M2BP) dc 76 information of using the state-of-the-art genomic or proteomic ap. the salivary mRNA as the biomarkers of OSCC approach.26 DUSP1 dl 87 HA3 dl 87 Saliva is preprogrammed to have a certain composition in re. and carcino-embryonic antigen (CEA) have been examined for detecting OSCC. For examples. there is ongoing development of these potential biomarkers include.81. CD44 dd 23 CD59 dd 76 To consider the sampling procedure and the complexity of the Cofilin-1 de 77 body fluids. a biomarker for breast cancer. hypermethylation on the promoter of DNA in spe- of OSCC. The most popular body fluids Potential biomarkers of OSCC in saliva. However. Bacteria dj 24 CD44 dk 23 Salivary proteomics DNA (promoter hypermethylation) dk 22. By using checkerboard DNA–DNA hybridiza. DNA polymorphism of IL-1b. 19) pro-inflammatory cytokine such as interleukin-6 (IL-6) and TNF-a. Interleukin 8 (IL-8) dc 80.

p6393 Active matrix metalloproteinase-745 "Tissue inhibitor of metalloproteinase-246 CD9792 . E-cadherin.E-cadherin61 "Trophoblast 247 .Fragile histidine triad89 CD9792 "p6371 "Keratin 849 Switching from E-cadherin to N-cadherin69 "RHAMM53 G2c Angiogenesis + p53 protein in central and peripheral region41 "Urokinase-type plasminogen activator receptor42.43 p16. Grading system Disease progression Low risk High risk Gxa Angiogenesis + p53 protein in central and peripheral region41 "Urokinase-type plasminogen activator receptor42. e G4 is defined as undifferentiated OSCC.228 J. and"Ki-6790 "Human telomerase reverse transcriptase63 Galectin-154 "p53 + .43 Syndecan-170 "Human telomerase reverse transcriptase63 "Tissue inhibitor of metalloproteinase-246 .Cellular syndecan-166. and Ki-6790 "Human telomerase reverse transcriptase63 Human telomerase reverse transcriptase63 "Tissue Inhibitor of metalloproteinase-246 Syndecan-170 .E-cadherin61 "Trophoblast 247 .E-cadherin with Delta Np63 and Delta Np73L94 Fragile histidine triad89 "CD10967 "CXCR456 .E-cadherin61 HIF-1 alpha88 "Trophoblast 247 MAGE-A1291 . b G1 is defined as well differentiated OSCC. gamma-catenin and Ki-6799 a Gx defined as differentiation of OSCC cannot be assessed.43 CD9792 "Human telomerase reverse transcriptase63 "Tissue inhibitor of metalloproteinase-246 . d G3 is defined as poorly differentiated OSCC.E-cadherin61 "Trophoblast 247 .43 p16. c G2 is defined as moderately differentiated OSCC.Cellular syndecan-166.Fragile histidine triad89 "p6371 "c-Met65 "Keratin 849 Switching from E-cadherin to N-cadherin69 "RHAMM53 G3d Angiogenesis + p53 protein in central and peripheral region41 "Urokinase-type plasminogen activator receptor42.E-cadherin61 "Trophoblast 247 . .70 "Ki-67 and"p53 at the deep tumor invasive front95 "p6371 "c-Met65 "Keratin 849 Switching from E-cadherin to N-cadherin69 "Aurora-B96 "RHAMM53 "Manganese superoxide dismutase 2 (SOD2)97 "Podoplanin98 "WNT-1 associated with beta-catenin. E-cadherin.43 HIF-1 alpha88 "Human telomerase reverse transcriptase63 "Tissue Inhibitor of metalloproteinase-246 .Fragile histidine triad89 "p6371 "Keratin 849 Switching from E-cadherin to N-cadherin69 "RHAMM53 G1b Angiogenesis + p53 protein in central and peripheral region41 "Urokinase-type plasminogen activator receptor42. p53. gamma –catenin and Ki-6799 G4e Active matrix metalloproteinase-745 "Urokinase-type plasminogen activator receptor42. Wu et al. / Oral Oncology 46 (2010) 226–231 Table 2 Biomarkers associated with histopathological grading of OSCC.-Y.70 "Ki-67 antigen and p53 at the deep tumor invasive front95 "p6371 "c-Met65 "keratin 849 Switching from E-cadherin to N-cadherin69 "Aurora-B96 "RHAMM53 "Manganese superoxide dismutase 2 (SOD2)97 "Podoplanin98 "WNT-1 associated with beta-catenin. p53.E-cadherin with Delta Np63 and Delta Np73L94 Fragile histidine triad89 "CD10967 "Cyclin B155 .

et al. Oral Oncol for the treatment of OSCC. The sensitive analytic method cussed. Chao SY. You SL.63 tissue inhibitor of metalloprotein. Palmisano WA. Hoque MO. primary screening test for high risk cases of OSCC since the collec- ing system. Zimmermann BG. Studies have shown that patients with activation of Akt. Wu et al. survival of patients with oral cancer. Jokinen K.60(21):5954–8. . However. OSCC.37 Therefore.58 and phosphorylated Akt.37 The histological grad. Simpson AJ.67 Akt activation. Salivary mRNA targets for cancer diagnostics. Jpn J Clin Oncol 2002. buccal mucosa preponderance. the cell with mild dysplasia that was unrecognized might undergo malig. development include tumor size.45 tis.36 expression of cellular syndecan-1 maybe the other group of poten- Therefore molecular pathology using the potential biomarkers for tial biomarkers to identify high-risk patients with OSCC. switching from E-cadherin to N-cadherin. Not only with proteins. grade. Hoque MO.73 In addition. Body fluid proteomics for biomarker discovery: lessons from the past hold the CD109. Prognostic H (CENP-H).-Y. G1.72. IL-6. Furthermore. autoantibodies against p53. 2004. the following 1. Baylin SB. Brinkman BM. and a close A.47 RhoC. has been identified Biomarkers for molecular pathology of OSCC in both saliva and serum. Huang SJ.42.36(6):525–8. Predicting lung cancer by detecting aberrant promoter methylation in sputum. Curr Opin Oncol 2006.64 c-Met. sue inhibitor of metalloproteinase-2. Cancer epidemiology and control in keratin 8. Kowalski LP. Parikka M. Soini Y. the markers with poor prognosis and survival rate in saliva of pa- tients with OSCC. Liu SA. imen is with low background and inhibitory substances and less moderately and poorly differentiated. the markers under high None declared. Bascands JL. surgery. Wong YK. which is aberrantly expressed in patients with OSCC. Generally. some pre-cancerous lesions may be the potential biomarkers for OSCC. J Formos Med Assoc 2007. etc. et al. 166 was associated with the recurrence of OSCC.59 and loss 6. gene which is a P53 gene homolog and the adverse expression of 9. Br J Cancer 2000. Clin Cancer Res 2008. Head Neck 2006. ificity in large sample size. extensively. Wong DT. the inhibition of Akt has been a molecular approach by microsatellite analysis in mouth washes and lesion brushings. cell carcinoma. / Oral Oncology 46 (2010) 226–231 229 identified in sera. risk category expressed in the oral squamous tissue at earlier stage (Gx.66. Distinctive features of oral cancer in nase-type plasminogen activator receptor. Kantola S. G2) indicates the tumor will become more malignant. based on the differentiation or maturation of the tumor cells which may fall from the cancerous tissue in the oral cavity.53 The in. Alho OP. 4. 11. Jeronimo C.62 could be a significant prognostic indicator for et al. Carvalho AL. Jeronimo C.17. Schanstra JP. et al. were associated with tumor metastasis may not be detectable in lated with OSCC tumor malignancy. J. N-cadherin. Thongboonkerd V. nosis and prognosis. Gilliland FD. histopathological factors. In fact. Lian Ie B. tin-1. as more and more bioinformatic success of the therapy (e. merase reverse transcriptase.46 interleukin IL-6 (IL-6).38. Yang YW. Nunes DN. in combined with molecular pathology analysis may improve the Traditional prognostic indicators and predict markers for cancer accuracy and staging diagnosis for OSCC. Cancer Res pression of p6371 in patients with OSCC had poorer survival rate.44(5):425–9. E-cadherin. J Proteome Res 2007. Mambo E.46 trophoblast 2. Disease mechanism and biomarkers of oral squamous ase-2.43 Ki-67 and VEGF- Changhua county: high incidence. keratin 8. Topaloglu O.28(11):998–1007.59 10. Although to dissect the extraordinary sion of OSCC. which was corre- lated with the recurrence of OSCC64 was also detected in sali- Histological examination remains a gold standard for diagnosis va. tumor. urine. the computation platform are generated. Evaluation of promoter hypermethylation detection in body fluids as a The elevation of the following biomarkers including human telo. the conventional analytic method.48 5.57 a protein encoded by P63 key to success in the future. Oral Oncol 2008.39 has been used tion procedure is non-invasive and low cost.g.):S66–81. Wong DT.41 These genes could be targeted to separate good and complex genetic or proteomic expression profile to find the ‘‘true” poor prognosis patients at the time of diagnosis and confirmed the biomarker remains a challenge. High levels of 8.59 2000.68 and P63. screening/diagnosis tool for head and neck squamous cell carcinoma. 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