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ISSN : 1226-7155(Print)
ISSN : 2287-6618(Online)
International Journal of Oral Biology Vol.50 No.1 pp.1-7
DOI : https://doi.org/10.11620/IJOB.2025.50.1.1

Salivary protein biomarkers for the early detection of oral cancers

Joungmok Kim1, Jeong Hee Kim1,2*
1Department of Oral Biochemistry and Molecular Biology, College of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea
2Department of KHU-KIST Converging Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
*Correspondence to: Jeong Hee Kim, E-mail:: jhkimh@khu.ac.krhttps://orcid.org/0000-0002-3884-4503
December 14, 2024 February 17, 2025 February 20, 2025

Abstract


Oral cancer has a high mortality rate, making early diagnosis crucial for effective treatment and prognosis. Unlike other cancers, oral cancer develops in the oral cavity, enabling direct contact between saliva and cancer cells. Therefore, saliva is a more useful diagnostic tool than serum or tissue. When DNA, RNA, or proteins produced by cancer cells enter the saliva, they can be easily detected as tumor markers. Therefore, salivary biomarkers can serve as a noninvasive alternative to serum- or tissue-based biomarkers. Early diagnosis is essential for increasing the treatment success rate, improving prognosis, and enhancing post-treatment recovery, ultimately improving the quality of life. Proteins are essential molecules involved in key processes, such as the development, growth, death, and metastasis of oral cancer. Recent advancements in molecular biology and salivary proteomics have enabled the detection and analysis of numerous proteins in saliva. Many of these protein molecules are currently the focus of extensive research. This article aims to review the potential of saliva as a diagnostic tool, techniques for detecting protein biomarkers, and salivary protein biomarkers for oral cancer diagnosis.


Oral cancer , Diagnostic , Saliva , Biomarkers

초록

    © The Korean Academy of Oral Biology. All rights reserved.

    This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Introduction

    Oral cancer has become a global health concern due to its notably high incidence and mortality rates [1]. Among oral cancers, more than 90% of cases are oral squamous cell carcinoma (OSCC) which represents over 40% of head and neck cancers and is the sixth most common cancer globally. The 5-year survival rate for late detection is only 30%, whereas, for early detection, it is over 90% [2]. Oral cancer is often diagnosed at an advanced stage, and the high mortality rate among patients is primarily attributed to delayed diagnosis [3]. This suggests the importance of early detection as one of the most effective strategies for improving treatment outcomes and prognosis of oral cancer.

    However, the use of serum biomarkers is limited due to their low diagnostic sensitivity and specificity in the early stages of oral cancer. Compared to blood or urine samples, salivary samples offer a more critical role in early diagnosis [4,5]. Therefore, saliva may be used as a specimen to bridge the gap that occurs using blood and urine as a marker and expedite the diagnostic process of oral cancer. In addition, saliva is collected locally from areas near oral cancers, allowing for the detection and analysis of tumor-specific biomolecules with minimal interference [4,5].

    Recently, there has been an increasing trend in the investigation of salivary biomarkers for oral diseases including oral cancers [4,6-8]. In this review, we focus on the protein biomarkers for the early detection of oral cancers. We will discuss the potential of saliva as a diagnostic specimen, the analytical techniques for protein biomarker detection, and the possibility of using salivary protein markers in oral cancer diagnostics.

    Saliva as an Alternative Diagnostic Body Fluid

    Human body fluids contain nucleic acids, proteins, peptides, and other components, making them ideal for disease diagnosis. Among these body fluids, saliva attracts attention because saliva collection procedures are straightforward, painless, safe, and noninvasive compared to other bodily fluids [9]. Biomarkers in saliva can represent both oral and systemic health, and similar to other bodily fluids, it can be analyzed to diagnose diseases.

    Saliva is a clear, slightly acidic (pH 6.6–7.1) liquid composed of 94–99% water and a small amount of various organic and inorganic components including water, ions, and proteins such as amylase, mucins, and immunoglobulins [10-12]. Though saliva is a heterogeneous mixture, it is used widely and successfully as a diagnostic specimen to identify various oral and systemic diseases including cancers, and viral infectious diseases including recently emerged coronavirus disease 2019 [13-15].

    Saliva primarily comes from the three major salivary glands ―the parotid, submandibular, and sublingual glands―which together account for about 85% of its composition. Other secreted saliva is derived from minor salivary glands [12]. Whole saliva also includes gingival crevicular fluid, plasma exudates, secretions from the upper respiratory tract, cell debris, and components of microorganisms, particularly bacteria [7,12]. Saliva is a complex biofluid that is increasingly recognized for its potential in investigating circulating cancer biomarkers. It offers enhanced specificity and sensitivity for diagnosis, prognostication, monitoring, and treatment of diseases. Saliva has a lower background of inhibitory substances and normal material than other body fluids, making it less complex than blood [16]. Compared to traditional biochemical analysis using tissue or blood samples, saliva analysis offers several advantages, including non-invasive and stress-free sample collection, ease of storage and transport, the ability for patients to self-supply samples, cost-effectiveness, and a lower risk of infection [7,17]. A large quantity of saliva samples can be collected and analyzed compared to tissue specimens. Due to the advantages of saliva samples and advancements in collection devices, saliva can be easily collected either at home or in a clinical setting, causing minimal disruption for participants [18,19]. To have saliva biomarkers to aid disease diagnostics, the importance of saliva collection, storage, and pretreatment methods should not be overlooked. The variables that may be involved in those processes should be minimized. Since saliva contains a wealth of biological information, there is growing interest in its use for various analyses.

    Saliva Proteins and Analysis Techniques

    Saliva contains a wide range of biomolecules, such as DNA, mRNA, proteins, metabolites, and microbiota. Advances in analytical techniques have enabled more rapid and precise identification of protein biomarkers in saliva, thereby advancing the field of salivaomics encompassing salivary genomes, transcriptomics, proteomics, metabolomics, microbiomics, and microRNA (miRNA) [20]. Recent advancements in analytical techniques have facilitated the use of salivary specimens for disease diagnosis.

    Proteomic approaches have profiled a wide range of polypeptides on a single platform. The proteomics platform primarily encompasses electrophoresis, chromatography, mass spectrometry, and immunological methods. Given the complexity and broad dynamic range of the salivary proteome, combining gel- and chromatography-based separation techniques with subsequent mass spectrometry (MS)-based analysis, alongside bioinformatics approaches, enables more efficient and accurate protein identification in biological samples. In addition, Human luminex multiplex assays, enzyme-linked immunosorbent assays (ELISA), and immunohistochemistry can be included [4,7,21].

    With the advancement of techniques, more than 3,000 proteins in saliva were identified, yielding the largest salivary proteomic dataset to date. This signifies a major advancement in the comprehensive exploration of the salivary proteome [22,23]. The salivary proteome of healthy individuals are identified and the data are publicly available via the Human Salivary Proteome Wiki (https://www.nidcr.nih.gov/sites/default/ files/2022-05/052022-HSP-Wiki.pdf) and Human Salivary Proteome (https://www.salivaryproteome.org/). Proteomic approaches remain costly, complex, and challenging to access. However, the development of simpler, more affordable, and efficient tools capable of analyzing small salivary samples holds promise for the early detection of various diseases. Saliva contains approximately 30% of the proteins found in blood, but certain salivary proteins, which serve specific functions, are exclusively produced in the oral cavity [24]. Though the concentrations of target substances are much lower than in blood, advancements in high-throughput analytical technologies have significantly enhanced the detection sensitivity and specificity of proteomic biomarkers in saliva [25].

    Salivary Biomarkers for Oral Cancers

    Oral cancer is a global health concern, characterized by high mortality rates and poor prognosis. Despite recent advances in biomedical research, early detection of oral cancer continues to be a challenge, and traditional diagnostic methods remain complex and often inaccurate. Identifying and quantifying noninvasive biomarkers in saliva presents a promising approach for early diagnosis, developing personalized therapeutic strategies, and monitoring disease progression in patients with oral cancer [7]. Among malignancies, oral cancer is the type in which salivary analysis offers significant advantages due to its direct interaction with cancer cells. Proteins associated with oral cancer, released either by oral cancer cells or by host immune cells, can directly enter the saliva and offer valuable information about oral cancer [20].

    Over 2,000 proteins and peptides associated with oral cancer and systemic diseases have been identified in saliva [26]. A comprehensive analysis of the salivary proteome can contribute to a deeper understanding of oral cancer and facilitate the identification of potential biomarkers for early, non-invasive detection and screening of the disease. Potential saliva biomarkers for oral cancer diagnostics are described below and summarized in Table 1.

    1. Enzymes

    A significant number of studies assessed salivary metalloproteinase (MMP) levels. A significantly higher salivary MMP- 9 levels were observed in OSCC patients [27]. Another study reported a significant difference in the salivary concentrations of MMP-9 and MMP-2 between oral potentially malignant disorders (OPMD) patients and controls [28]. Other MMPs including MMP-1, MMP-3, MMP-10, MMP-12, and MMP-13 have also been reported to be altered between healthy and OSCC patients [6,29].

    Among other enzymes that showed higher levels in OSCC patients, lactate dehydrogenase (LDH) is the most extensively studied [30]. A significant increase in LDH levels was reported in OSCC and high-risk premalignant lesions compared to the control groups [31]. Human pancreatic α-amylase and human salivary amylase have been identified as potential salivary biomarkers for OSCC, although additional validations are needed [32].

    2. Cytokines and glycoproteins

    Cytokines are small and soluble glycoproteins that are released in response to stimuli such as infection or inflammation. The expression of cytokines such as interleukin (IL)-1β and IL-8 was increased in the saliva of patients with OSCC [33,34]. Similarly, a study with 180 patients revealed that IL-1β and IL-8 were elevated compared with control patients [35]. In addition, IL-6, tumor necrosis factor (TNF)-α, and vascular endothelial growth factor-A are notably elevated in the saliva of OSCC patients [34,36].

    Other cytokines including IL-4, IL-10, IL-13, IL-1RA, IL- 17A, IL-17F, interferon-γ, hepatocyte growth factor, and Creactive protein are increased in their expression in saliva [37,38]. Among these cytokines, the most studied cytokine was IL-8. Many studies reported a significant increase in IL-8 levels in the saliva of OSCC patients compared to the controls [39-41]. TNF-α was also among the cytokines examined in a considerable number of studies. It has been reported that TNF-α concentrations in OSCC patients’ saliva are significantly higher than those in control patients [39,42].

    A glycoprotein, Mac-2-binding protein (M2BP) has been identified as a salivary biomarker of oral cancer. M2BP showed much higher expression in OSCC patients using immunoassays [43]. Podoplanin is a mucin-type glycoprotein commonly used as a marker for lymphatic endothelial cells. Inoue et al. [44] revealed that podoplanin-positive stromal fibroblasts were detected in 73.9% of the primary OSCC patients.

    3. Cluster of differentiation

    Cluster of differentiation (CD)44 and CD59 are reported as probable biomarkers for head and neck cancer and OSCC [43]. CD44 is a cell surface glycoprotein that plays a key role in cellto- cell interactions. It acts as an adhesion receptor, widely expressed in various cancers, and regulates metastasis by recruiting CD44 to the cell surface. CD59, also known as MAC inhibitory protein or protectin, is a glycoprotein that binds to host cells through a glycosylphosphatidylinositol anchor.

    4. Others

    Saliva from OSCC patients has been shown to contain several protein markers. Endothelin-1 was found to be a possible biomarker for oral cancer development [45]. In an earlier study, a soluble fragment of cytokeratin 19 (CYFRA21-1) was described as a potential biomarker for oral cancer [46]. A recent systematic review found that CYFRA21-1 was the only protein capable of distinguishing between patients with OPMD and healthy controls [47]. Recently, levels of cellular prion protein (PrPc) in saliva and serum were found to be significantly elevated in OSCC patients compared to the control group. Based on these findings, Zheng et al. [48] proposed PrPc as a potential biomarker for the early detection of oral cancer. In studies using fluorescent immunoassay or electric biosensors, it was found that carcinoembryonic antigen levels in saliva showed a significant difference between patients and healthy individuals [49].

    Conclusion

    Saliva has great potential for monitoring overall health and disease, offering unique opportunities for clinical applications. It is advantageous due to its simplicity, safety, costeffectiveness, and non-invasive nature. Additional research is needed to determine the clinical usefulness, standardization, and accuracy of salivary biomarkers. Future research should include larger clinical studies and focus on further validating and improving the diagnostic and monitoring potential of salivary biomarkers, ultimately offering a valuable and convenient tool for clinical practice.

    Funding

    No funding to declare.

    Conflicts of Interest

    No potential conflict of interest relevant to this article was reported.

    Figure

    Table

    Potential saliva biomarkers for oral cancer diagnostics

    MMP, metalloproteinase; OSCC, oral squamous cell carcinoma; OPMD, oral potentially malignant disorders; LDH, lactate dehydrogenase; IL, interleukin; TNF-α, tumor necrosis factor-α; VEGF-A, vascular endothelial growth factor-A; IL-1RA, interleukin-1 receptor antagonist; IFN-γ, interferon-γ; HGF, hepatocyte growth factor; CRP, C-reactive protein; M2BP, Mac-2-binding protein; CD, cluster of differentiation; CYFRA21-1, soluble fragment of cytokeratin 19; PrPc, cellular prion protein; CEA, carcinoembryonic antigen.

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