|
 
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| REVIEW ARTICLE |
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| Year : 2017 | Volume
: 29
| Issue : 4 | Page : 300-305 |
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Genomic Alphabets of Saliva as a Biomarker in Oral Cancer
Govindraju Poornima, Talkad Subbaiah Mahesh Kumar
Department of Oral Medicine and Radiology, Rajarajeswari Dental College and Hospital, Bengaluru, Karnataka, India
| Date of Submission | 01-Aug-2016 |
| Date of Acceptance | 29-Jan-2018 |
| Date of Web Publication | 15-Feb-2018 |
Correspondence Address:
Dr. Talkad Subbaiah Mahesh Kumar
Department of Oral Medicine and Radiology, #14, Rajarajeswari Dental College and Hospital, Ramohalli Cross, Mysore Road, Bengaluru - 560 074, Karnataka
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jiaomr.JIAOMR_90_16
 Abstract | | |
Oral cancer is one of the most common cancers in the developing world with high mortality rate despite the recent advances in diagnosis and treatment. The major reason for low survival rate is late diagnosis. Salivary diagnostics is an emerging field along with the application of genomics aiding in the early detection of oral cancer. These genomic alphabets of saliva may serve as a timely, cost effective, noninvasive diagnostic medium. This article aims to discuss the role of genomic alphabets of saliva in the diagnosis of oral cancer.
Keywords: Biomarker, oral cancer, saliva
How to cite this article:
Poornima G, Mahesh Kumar TS. Genomic Alphabets of Saliva as a Biomarker in Oral Cancer. J Indian Acad Oral Med Radiol 2017;29:300-5 |
How to cite this URL:
Poornima G, Mahesh Kumar TS. Genomic Alphabets of Saliva as a Biomarker in Oral Cancer. J Indian Acad Oral Med Radiol [serial online] 2017 [cited 2023 Feb 3];29:300-5. Available from: http://www.jiaomr.in/text.asp?2017/29/4/300/225569 |
| Introduction | |  |
One of the major global public health problems is oral cancer which accounts for one-third of the burden of Indian subcontinent, ranking sixth among all cancers.[1],[2] The morbidity and the disappointing survival rate may be attributed to diagnostic delay as most oral cancers are asymptomatic in their initial stages.[3],[4] Oral cavity is an important part of the body; multiple structures and tissue are working in this intricate environment. Oral cancer has an increased incidence in comparison to other cancers in various anatomical sites particularly in younger individuals and women.[5] The changes in the incidence of oral cancer cannot be explained purely by tobacco and alcohol consumption, which are considered major risk factors because oral cancer may also be observed in individuals who are free of these habits.[6]
The genetic aberration of cancer cells leads to altered gene expression patterns, which can be identified long before the resulting cancer phenotypes are manifested. These changes are unique in cancer in comparison with that of normal tissue of same origin, hence, this can be utilized as molecular biomarkers.[7] The main aim of oral cancer screening is to diagnose oral cancer at an early stage for effective treatment and better prognosis. Hence, screening tests that disclose the combination of increased sensitivity and increased specificity are required; moreover, the screening tool must be sufficiently noninvasive and cost-effective and timely available to allow widespread applicability. Outstanding development of biotechnology and development in the basic understanding regarding cancer initiation and progression has empowered us in identifying tumor signatures such as oncognes and tumor suppressor gene alterations in bodily fluids that drain from the organs affected by the tumor.[8]
Application of genomics and the knowledge of the sequence of human genome have inspired numerous -omics disciplines such as proteomics, epigenomics, transcriptomomics, glycomics, and metabolomics enabling us to understand the signaling pathways of the cell and thereby provide valuable insight into the pathogenesis of disease leading to identification of new prognosticators, diagnostic markers, and therapeutic targets.[9] Biomarkers are defined as cellular, biochemical, molecular, or genetic alterations by which a normal, abnormal, or simply biologic process can be recognized or monitored. Tissues, cells, or any body fluid can be a biomarker which may be secreted by the malignancy or due to specific response of the body as a result of the malignancy.[10]
These biomarkers are important indicators of physiological or pathological conditions and provide information for the detection of early and differential markers for disease. Cognizing and assessing the importance of an individual biomarker signature may help in establishing the presence, location, and likelihood of disease. Hence, these biomarkers can be considered as valuable tools in early detection, assessing risk, diagnosis, prognosis, and disease monitoring. Of these biomarkers saliva is one such important biomarker.[11] Saliva, an unique, complex body fluid, also referred as mirror of the body health, is a biological fluid secreted by the three major salivary glands (parotid, submandibular, and sublingual), minor glands, and gingival crevicular fluid.[12],[13]
The various chemical components of saliva include water, inorganic compounds (ions), organic compounds (nonproteins and lipids), protein/polypeptides, and hormones, and an array of analytes.[12],[14] On an average, an individual salivary flow rate can vary from 0.3 to 0.7 ml of saliva per minute producing a range of 1 to 1.5 liters daily.[15],[16] Saliva is multifunctional, serving not only to facilitate digestion, swallowing, tasting, and tissue lubrication but also as a protective barrier against pathogens.[17],[18] Most common diagnostic biomarker used is serum but saliva can also be used as an alternate to serum as it has numerous advantages in comparison to serum.[19] Collection of sample is undemanding, noninvasive, safer to handle,[20] easier to ship and store, and the procedure is economical.[21] Saliva also comprises inhibitory substances as well as fewer complexes than blood.[22]
There are five major diagnostic alphabets available namely, proteins, mRNAs, miRNAs, metabolic compounds, and microbes which offer substantial advantages for salivary diagnostics because the state of the disease may be associated with detectable changes in one, but not all, dimensions.[23] The salivary biomarkers are also classified based on the mechanism of action [24] [Table 1]. Human saliva is composed of varied amount of diverse proteins, each with particular biological characteristics. Even though the proteomic content of saliva was found to be only 30% that of blood,[25] saliva is actively being investigated as a major source of protein biomarkers.[26] More than 2300 minor proteins or peptides are present in saliva defining the first salivary biomarker alphabet.[27],[28] | Table 1: Classification of Salivary biomarkers depending on the level of action at molecular level
Click here to view |
Salivary proteome
The most plentiful proteins includes α-amylase, albumin, cystatins, hystatins, secretory-IgA, lactoferrin, mucins, lysozymes, proline rich proteins, statherin and transferrin which together account for more than 98% of the total salivary proteins.[29] Salivary proteins are involved in a number of metabolic pathways, including amino acid-related metabolism, carbohydrate metabolism, energy metabolism, and glycan biosynthesis, and metabolism. Interestingly, several salivary proteins were found in a few systemic diseases, such as amyloid beta A4 protein precursor (Alzheimer's), DJ-1 (Parkinson's diseases), and colon cancer secreted protein-2 (colorectal cancer). The sequential amino acid in a protein provides a link between the proteins and their respective coding genes through genetic code, and this protein complement of the genomics known as the proteome.[30]
The presence of these salivary proteomic markers in low concentration plays a major role in the discrimination of diseases. Proteomic studies of human saliva constitutes four major salivary families of specific secretory proteins – proline-rich proteins (PRPs), statherins, and cystatins – and these secretory proteins differ significantly from the host defense salivary proteins as these have a particular function in the oral cavity.[31] Even though the proteomic constituents are considered as the logical first choice as salivary diagnostic analytics, the genomic targets are considered as highly discriminatory and informative. Analysis of the salivary proteomes may reveal morbidity signatures in the early stage and monitor disease progression. Cyfra 21.1, tissue polypeptide antigen (TPA), and cancer antigen (CA125) are elevated in saliva when compared to the sera [Table 2].[32],[33] | Table 2: Classification of the salivary biomarker of oral cancer depending on the genomic alphabets
Click here to view |
IL-1, IL-6 IL-8, TNF-a: These proangiogenic, proinflammatory cytokines are elevated in whole saliva of oral cancer patients and oral precancers compared to controls which suggests its utility as surrogate indicators of carcinogenic transformation from oral precancer to oral cancer. The alterations in salivary IL-6 and TNF-a might play a significant role in the development of oral leukoplakia.
Transferrin: Salivary transferrin levels were found to be in strong correlation with the size and stage of the tumor in oral cancer patients. MRP14 is overexpressed in tongue cancer, M2BP, MRP14, CD59, catalase, and profiling detects oral cancer with a sensitivity of 90% and specificity of 83% [Table 2].[34]
Salivary transcriptome
Apart from proteins, saliva also contain nucleic acids thus considered as the second alphabet,[27] Messenger (m) RNA is the direct precursor of proteins and in general the corresponding levels are correlated in cells and tissue samples. More than 3000 mRNAs are present in the human saliva, out of which 180 are common between different normal participants constituting the normal salivary transcriptome core.[35],[36]
When compared to DNA, RNA is more labile and is highly susceptible to degradation by the RNases and in cancer patients this RNase activity is elevated; thus, it is hypothesized that human mRNA could not survive extracellularly in saliva. However, with the advances in PCR, i.e., reverse transcription (RT)-PCR human mRNA can be analyzed, improving the salivary diagnostics.[34],[36] The most common mRNA significantly higher in oral cancer are IL8, IL1B, and ferritin polypeptide [Table 1] and [Table 2].[37],[38]
IL8: Interleukin 8 regulates angiogenesis, replication, calcium-mediated signalling pathway, cell adhesion, chemotaxis, cell cycle arrest, and immune response.
Transcriptome DUSP1 (dual specificity phosphatase 1): This functions by protein modification, signal transduction, oxidative stress, H3F3A H3 histone, family 3A helps in DNA binding.
IL1B (interleukin 1β): This functions as signal transduction, helps in proliferation, inflammation, and apoptosis.[37]
OAZ1 (ornithine decarboxylase antizyme 1): It is an antizyme targeting ornithine decarboxylase for degradation, subsequently inhibiting polyamine production to prevent cell proliferation. OAZ1 is also involved in other major cellular events, including differentiation and apoptosis. Recent studies have shown that OAZ1 has tumor suppressor activities and its effects on cell proliferation and differentiation have been reported in several cancer cell lines.[39] SAT (spermidine/spermine N1-acetyltransferase): Multiple abnormalities in the control of polyamine metabolism and uptake might be responsible for increased levels of polyamines in cancer cells as compared to that of normal cells.[40]
S100P (S100 calcium binding protein P): Dysregulated expression of multiple members of the S100 family is a common feature of human cancers, with each type of cancer showing a unique S100 protein profile or signature. Emerging in-vivo evidence indicates that the biology of most S100 proteins is complex and multifactorial, and that these proteins actively contribute to tumorigenic processes such as cell proliferation, metastasis, angiogenesis, and immune evasion.[41]
Salivary microRNA
MicroRNAs (MiRNAs) are small single stranded RNA encoded by genes but are not translated into proteins. They are noncoding RNAs; instead each primary transcript (a pri-mi RNA) is processed into a short stem loop structure as a pre-miRNA and finally into a functional miRNA.[28] The study of the presence of miRNAs in human saliva is an emerging field in monitoring oral diseases with the help of salivary diagnostics. miRNAs are short noncoding RNA molecules measuring 19–25 nt in length; it was first invented in 1993 as small RNAs in Caenorhabditis elegans.[39],[42] Thereafter, miRNAs have been categorized based on the mass and the biogenesis of miRNAs and their mode of action. miRNAs binding to complementary sequences in the 3′-untranslated region (3′-UTR) of mRNAs to regulate gene expression by inhibiting protein translation and/or causing mRNA degradation, miRNAs play important roles in regulating various cellular processes such as cell growth, differentiation, apoptosis, and immune response.[43],[44]
Over 2500 miRNAs are known in the human genome and over 30% of human mRNAs are post-transcriptionally regulated by miRNAs.[42] In saliva, miRNAs were found present in both whole saliva and saliva supernatant. In addition to the combined approach of transcriptomics and proteomics, miRNA constitutes the third diagnostic alphabet in saliva. Any dysregulation in expressing these miRNA will adversely affect the cell growth and acts like a tumor suppressor or oncogene in many cancers.[45] In oral cancer, miRNAs have been shown to affect cell proliferation,[43] apoptosis,[46] and even chemotherapy resistance in OSCC patients,[47] miRNAs have also been observed in OSCC to be epigenetically regulated by DNA methylation [Table 2].[48],[49],[50]miR125, a gene, plays an important role in cell proliferation and can affect the genes involved in MAPK metabolism; miR200a genes levels are downregulated during metastasis and can be inversely correlated to the degree of invasion. miR31 gene levels are completely lost in metastatic tumors.[51]
Salivary metabolome
The collection of small molecules present in cells, tissues, organs, and biological fluids is known as metabolome, and the study of metabolome is metabolomics.[51],[52] The metabolome validates the parallel assessment of a group of endogenous and exogenous metabolites, including lipids, amino acids, peptides, nucleic acids, organic acids, vitamins, thiols, and carbohydrates and is a valuable tool for discovering biomarkers, monitoring physiological status, and making proper treatment decisions [Table 2].[53],[54] Wei et al. found that a combination of three salivary metabolites (phenylalanine, valine, and lactic acid) could distinguish OSCC patients from healthy controls with high sensitivity and high specificity (86.5% and 82.4%) and oral leukoplakia (OLK) patients (94.6% and 84.4%). Taurine and piperidine are considered as the oral cancer specific diagnostic marker.[55]
Salivary microbiome
The hard and soft tissues in the oral cavity are colonized by bacteria and gets constantly bathed in saliva.[56],[57] Oral microbiome is constituted by proportionately a minute number of bacterial phyla, of which the commonly reported abundant phyla are Firmictes, Proteobacteria, Bacteroidetes, Actinobacteria, and Fusobacteria [Table 2].[58],[59] The majority of interindividual variation has been personated because of diversity at the species or strain level.[60]Streptococcus is routinely observed to be the dominant genus in the healthy oral microbiome and commonly Prevotella, Veillonella, Neisseria, and Haemophilus dominate an individual's oral microbiome.[61] Variation is also observed in the microbial community composition of biofilms at each intraoral habitat (e.g., teeth surface, lateral and dorsal surface of tongue, etc.), most likely reflecting the different surface properties and microenvironments.[62],[63]
Even though certain studies report that 700 to 1,200 bacterial species reside in the mouth,[64],[65] investigators using next-generation sequencing (NGS) suggest that this number could be as high as 10,000.[65],[66],[67] Although many individuals shelter only about 75 to 100 predominant species of bacteria which are known to inhabit the oral cavity 35% to 50% of those have yet to be cultivated. Understanding of the alterations in the oral microbiome are related to local and systemic disorders which provides a critical input regarding disease pathogenesis, diagnosis, monitoring, and prognosis.[68] Establishing disease-specific microbiological signatures could lead to the development of simple tests targeting discriminatory microbes capable of identifying particular pathologies. Early detection, especially in population with high risk, is indicated for more expeditious therapeutic interventions which may inhibit the progression or even the onset of pancreatic cancer and other disorders, leading to more positive outcomes.[57],[69]Capnocytophaga gingivalis, Prevotella melaninogenica, and Streptococcus mitis can be used as diagnostic markers to distinguish OSCC from healthy subjects with 80% sensitivity and 82% specificity.[55]
A vast amount of Omic-based salivary data has been generated with the use of high throughput technologies, but there are some barriers to exploit such data and saliva has not been extensively interspersed in ontology and terminology resources. So recently, the Salivaomics Knowledge Base (SKB) has been established by aligning the salivary biomarker discovery. The SKB constitutes data repository, management system, and web resource fabricated to support human salivary proteomics, transcriptomics, miRNA, metabolomics, and microbiome research. The SKB provides the first web resource dedicated to salivary “omics” studies. This comprises the major data and information required to explore the biology, diagnostic potentials, pharmacoproteomics, and pharmacogenomics of human saliva.[70]
SALO is a consensus-based controlled vocabulary of terms and relations dedicated to the salivaomics domain and to saliva-related diagnostics. This is intended to meet the needs of both the clinical diagnostic community and the crossdisciplinary community of researchers.[71] With these significant advances, salivary biomarkers are developing; however some challenges exist with the use of salivary biomarkers:
- A lack of standardization of conditions and methods of saliva sample collection, processing, and storage
- Variability in the levels of potential salivary biomarkers in both non-cancerous individuals and oral cancer patients, suggest unknown confounding factors
- The need for further validation of oral cancer salivary biomarkers.[72]
Single biomarker detection is not effective enough for accurate diagnosis and medical decisions because of the complexity of the human biological system and the high possibility of false positive and false negative rates. The combination of multiple biomarkers could include nucleic acids which are highly discriminatory, proteins and small molecules like metabolites.[27]
| Conclusion | | |
The rapid development and maturity of the genomics field along with improved biotechnology and expanded research has resulted in the emergence of different omics studies. With the advent of these salivary diagnostics, it has been an effective and promising modality for early diagnosis, prognostication, and post-therapy status monitoring in oral cancer.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Chi AC. Squamous cell carcinoma. In: Neville BW, Damm DD, Allen CM, Bouquot JE, editors. Oral and Maxillofacial Pathology. St. Louis: Saunders Elsevier: 2009. p. 409-21.  |
| 2. | Khalili J. Oral cancer: Risk factors, prevention and diagnostic. Exp Oncol 2008;30:259-64. [ PUBMED] |
| 3. | Wildt J, Bundgaard T, Bentzen SM. Delay in the diagnosis of oral squamous cell carcinoma. Clin Otolaryngol 1995;20:21-5. [ PUBMED] |
| 4. | Peacock ZS, Pogrel MA, Schmidt BL. Exploring the reasons for delay in treatment of oral cancer. J Am Dent Assoc 2008;139:1346-52. [ PUBMED] |
| 5. | Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin 1999;49:33-64. [ PUBMED] |
| 6. | Schmidt BL, Dierks EJ, Homer L, Potter B. Tobacco smoking history and presentation of oral squamous cell carcinoma. J Oral Maxillofac Surg 2004;62:1055-8. [ PUBMED] |
| 7. | Sidransky D. Emerging molecular markers of cancer. Nat Rev Cancer 2002;2:210. [ PUBMED] |
| 8. | Sidransky D. Nucleic acid-based methods for the detection of cancer. Science (Wash DC) 1997;278:1054-9. |
| 9. | Tanke HJ. Genomics and proteomics. The potential role of oral diagnostics. Ann N Y Acad Sci 2007;1098:330-4. [ PUBMED] |
| 10. | Baum BJ, Yates III JR, Srivastava S, Wong DTW, Melvin J E. Scientific frontiers: Emerging technologies for salivary diagnostics. Adv Dent Res 2011;23:360-8. |
| 11. | Kurian S, Grigoryev Y, Head S, Campbell D, Mondala T, Salomon DR. Applying genomics to organ transplantation medicine in both discovery and validation of biomarkers. Int Immunopharmacol 2007;7:1948-60. [ PUBMED] |
| 12. | Castagnola M, Picciotti PM, Messana I, Fanali C, Fiorita A, Cabras T, et al. Potential applications of human saliva as diagnostic fluid. Acta Otorhinolaryngol Ital 2011;31:347-57. [ PUBMED] |
| 13. | 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. Indian J Clin Biochem 2011;26:326-34. [ PUBMED] |
| 14. | Chiappin S, Antonelli G, Gatti R, De Palo EF. Saliva specimen: A new laboratory tool for diagnostic and basic investigation. Clin Chim Acta 2007;383:30-40. [ PUBMED] |
| 15. | Edgar W. Saliva and dental health. Br Dent J 1990;169:96-8. |
| 16. | Chicharro JL, Lucia A, Perez M, Vaquero AF, Urena R. Saliva composition and exercise. Sports Med 1998;26:17-27. |
| 17. | Segal A, Wong DT. Salivary diagnostics: Enhancing disease detection and making medicine better. Eur J Dent Educ 2008;12(suppl 1):22-9. [ PUBMED] |
| 18. | Mandel ID. Salivary diagnosis: More than a lick and a promise. J Am Dent Assoc 1993;12:85-7. |
| 19. | Johnson LR. Salivary Secretion. Gastrointestinal Physiology. 6 th Ed. St. Louis, MO, USA: Mosby; 2001. p. 65-74. |
| 20. | Campo J, Perea MA, Del Romero J, Cano J, Hernando V, Bascones A. Oral transmission of HIV, reality or fiction? An update. Oral Dis 2006;12:219-28. [ PUBMED] |
| 21. | 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. [ PUBMED] |
| 22. | Zimmermann BG, Park NJ, Wong DT. Genomic targets in saliva. Ann NY Acad Sci 2007;1098:184-91. [ PUBMED] |
| 23. | Wong DT. Salivomics. J Am Dent Assoc 2012;143(10 suppl):19S-24S. |
| 24. | Markopoulos AK, Michailidou EZ, Tzimagiorgis G. Salivary markers for oral cancer detection. The Open Dent J 2010;4:171-8. |
| 25. | Schulz BL, Cooper-White J, Punyadeera CK. Saliva proteome research: Current status and future outlook. Crit Rev Biotechnol 2012;33:246-59. [ PUBMED] |
| 26. | Kawas SA, Rahim ZHA, Ferguson DB. Potential uses of human salivary protein and peptide analysis in the diagnosis of disease. Arch Oral Biol 2012;57:1-9. |
| 27. | Spielmann N, Wong DT. Saliva: Diagnostics and therapeutic perspectives. Oral Dis 2011;17:345-54. [ PUBMED] |
| 28. | Bandhakavi S, Stone MD, Onsongo G, Van Riper SK, Griffin TJ. A dynamic range compression and three-dimensional peptide fractionation analysis platform expands proteome coverage and the diagnostic potential of whole saliva. J Proteome Res 2009;8:5590-600. [ PUBMED] |
| 29. | Messana I, Inzitari R, Fanali C, Cabras T, Castagnola M. Facts and artifacts in proteomics of body fluids. What proteomics of saliva is telling us? J Sep Sci 2008;31:1948-63. [ PUBMED] |
| 30. | Hassaneen M, Maron JL. Salivary diagnostics in pediatrics: Applicability, translatability, and limitations. Front Public Health 2017;5:83. |
| 31. | Lamkin MS, Oppenheim FG. Structural features of salivary function. Crit Rev Oral Biol Med 1993;4:251-9. [ PUBMED] |
| 32. | Lee Y, Wong DT. Saliva. An emerging biofluid for early detection of diseases. Am J Dent 2009;22:241-8. |
| 33. | Wong DT. Salivary diagnostics powered by nanotechnologies, proteomics and Genomics. J Am Dent Assoc 2006;137:313-21. [ PUBMED] |
| 34. | Hu S, Arellano M, Boontheung P, Wang J, Zhou H, Jiang J, et al. Salivary proteomics for oral cancer biomarker discovery. Clin Cancer Res 2008;14:6246-52. [ PUBMED] |
| 35. | Li Y, Zhou X, St John MA, Wong DT. RNA profiling of cell free saliva using microarray technology. J Dent Res 2004;83:199-203. [ PUBMED] |
| 36. | Park NJ, Zhou H, Elashoff D, Henson BS, Kastratovic DA, Abemayor E, et al. Salivary microRNA: Discovery, characterization, and clinical utility for oral cancer detection. Clin Cancer Res 2009;15:5473-7. [ PUBMED] |
| 37. | Li Y, St John MAR, Zhou X, Kim Y, Sinha U, Jordan RCK, et al. Salivary transcriptome diagnostics for oral cancer detection. Clin Cancer Res 2004;10:8442-50. |
| 38. | Zimmermann BG, Wong DT. Salivary mRNA targets for cancer diagnostics. Oral Oncol 2008;44:425-9. [ PUBMED] |
| 39. | 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. [ PUBMED] |
| 40. | Thomas T, Thomas TJ. Polyamine metabolism and cancer. J Cellular Mol Med 2003;7:113-26. |
| 41. | Bresnick AR, Weber DJ, Zimmer DB. S100 proteins in cancer. Nat Rev Cancer 2015;15:96-109. [ PUBMED] |
| 42. | Bartel DP. MicroRNAs: Target recognition and regulatory functions. Cell 2009;136:215-33. [ PUBMED] |
| 43. | Bartel DP. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 2004;116:281-97. [ PUBMED] |
| 44. | Sekuklu SD, Donoghue MTA, Spillane C. miR-21as a key regulator of oncogenic processes. Biochem Soc Trans 2009;37:918-25. |
| 45. | Wong TS, Liu XB, Wong BYH, Ng RWM, Yuen APW, Wei WI. Mature miR-184 as potential oncogenic microRNA of squamous cell carcinoma of tongue. Clin Cancer Res 2008;14:2588-92. |
| 46. | Varol N, Konac E, Gurocak OS, Sozen S. The realm of micro RNAs in cancers. Mol Biol Rep 2010;38:1079-89. [ PUBMED] |
| 47. | Yu ZW, Zhong LP, Ji T, Zhang P, Chen WT, Zhang CP. Micro RNAs contribute to chemoresistance of cisplatin in tongue squamous cell carcinoma lines. Oral Oncol 2010;46:317-22. [ PUBMED] |
| 48. | Kozaki K, Imoto I, Mogi S, Omura K, Inazawa J. Exploration of tumor suppressive microRNAs silenced by DNA hypermethylation in oral cancer. Cancer Res 2008;68:2094-105. [ PUBMED] |
| 49. | Yoshizawa JM. Wong DT. Salivary micro RNAs and oral cancer detection methods. Mol Biol 2013;936:313-24. |
| 50. | Kim S, Lee S, Lee Y. Micro RNAs as biomarkers for dental diseases. Singapore Dent J 2015;36:18-22. |
| 51. | Panta P, Venna VR. Salivary RNA signatures in oral cancer detection. Anal Cell Pathol (Amst) 2014;2014:450629. [ PUBMED] |
| 52. | Aharoni A, Verhoeven HA, Maliepaard CA, Maliepaard CA, Kruppa G, Bino R, et al. Nontargeted metabolome analysis by use of Fourier transform ion cyclotron mass spectrometry. OMICS 2002;6:217-34. [ PUBMED] |
| 53. | Dettmer K, Hammock BD. Metabolomics-- A new exciting field within the “omics” sciences. Environ Health Perspect 2004;112:A396-7. [ PUBMED] |
| 54. | Takeda I, Stretch C, Barnaby P, Bhatnager K, Rankin K, Fu H, et al. Understanding the human salivary metabolome. NMR Biomed 2009;22:577-84. [ PUBMED] |
| 55. | Zhang Y, Sun J, Lin C, Abemayor E, Wang MB, Wong DT. The emerging landscape of salivary diagnostics. Oral Health Dent Manag 2014;13:200-10. |
| 56. | Wei J, Xie G, Zhou Z, Shi P, Qiu Y, Zheng X, et al. Salivary metabolite signatures of oral cancer and leukoplakia. Int J Cancer 2011;129:2207-17. [ PUBMED] |
| 57. | 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. [ PUBMED] |
| 58. | Nasidze I, Li J, Quinque D, Tang K, Stoneking M. Global diversity in the human salivary microbiome. Genome Res 2009;19:636-43. [ PUBMED] |
| 59. | 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. [ PUBMED] |
| 60. | Bik EM, Long CD, Armitage GC, Loomer P, Emerson J, Mongodin EF, et al. Bacterial diversity in the oral cavity of 10 healthy individuals. ISME J 2010;4:962-74. [ PUBMED] |
| 61. | Aas JA, Paster BJ, Stokes LN, Olsen I, Dewhirst FE. Defining the normal bacterial flora of the oral cavity. J Clin Microbiol 2005;43:5721-32. [ PUBMED] |
| 62. | Zaura E, Keijser BJ, Huse SM, Crielaard W. Defining the healthy “core microbiome” of oral microbial communities. BMC Microbiol 2009;9:259. [ PUBMED] |
| 63. | 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. [ PUBMED] |
| 64. | Griffen AL, Beall CJ, Firestone ND, Gross EL, Difranco JM, Hardman JH, et al. CORE: A phylogenetically-curated 16S rDNA database of the core oral microbiome. PLoS One 2011;6:e19051. [ PUBMED] |
| 65. | Nasidze I, Quinque D, Li J, Li M, Tang K, Stoneking M. Comparative analysis of human saliva microbiome diversity by barcoded pyrosequencing and cloning approaches. Anal Biochem 2009;391:64-8. [ PUBMED] |
| 66. | Mandel I. The function of saliva. J Dent Res 1987;66:623-7. |
| 67. | Keijser BJF, Zaura E, Huse SM, van der Vossen JM, Schuren FH, Montijn RC, et al. Pyrosequencing analysis of the oral microflora of healthy adults. J Dent Res 2008;87:1016-20. |
| 68. | Mager D, Haffajee A, Devlin P, Norris C, Posner M, Goodson J. 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. |
| 69. | Paju S, Pussinen P, Suominen-Taipale L, Hyvönen M, Knuuttila M, Könönen E. Detection of multiple pathogenic species in saliva is associated with periodontal infection in adults. J Clin Microbiol 2009;47:235-8. |
| 70. | Ai J, Smith B, Wong DT. Saliva ontology: An ontology-based framework for a Salivaomics Knowledge Base. BMC Bioinform 2010;11:302. |
| 71. | Ai J, Smith B, Wong DT. Bioinformatics advances in saliva diagnostics. Int J Oral Sci 2012;4:85-7. |
| 72. | Cheng YL, Rees T, Wright J. A review of research on salivary biomarkers for oral cancer detection. Clin Transl Med 2014;3:3. |
[Table 1], [Table 2]
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