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The relationship between salivary cytokines and oral cancer and their diagnostic capability for oral cancer: a systematic review and network meta-analysis

BMC Oral Health volume 24, Article number: 1044 (2024) Cite this article

Abstract

Background

Oral cancer (OC) is a common malignancy in clinical practice. Saliva testing is a convenient and noninvasive early diagnostic technique for OC. Several salivary cytokines have been identified as potential biomarkers for OC, including IL-8, IL-6, TNF-α, IL-1β, and IL-10. Nonetheless, the optimal cytokine for OC diagnosis remains inconclusive and highly contentious.

Methods

PubMed, Embase, Web of Science, and Cochrane Library databases were comprehensively retrieved to collect all case–control studies on OC. A meta-analysis was performed to compare the levels of salivary IL-8, IL-6, IL-10, TNF-α, and IL-1β in OC patients and healthy controls. Network meta-analysis (NMA) was carried out to probe into the accuracy of these salivary cytokines in diagnosing OC.

Results

This analysis included 40 studies, encompassing 1280 individuals with OC and 1254 healthy controls. Significantly higher levels of salivary IL-8, IL-6, TNF-α, IL-1β, and IL-10 were observed in patients with OC in comparison to healthy controls. The results of NMA showed that TNF-α had the highest diagnostic accuracy for OC, with a sensitivity of 79% and a specificity of 92%, followed by IL-6 (sensitivity: 75%, specificity: 86%) and IL-8 (sensitivity: 80%, specificity: 80%).

Conclusion

This study suggests that IL-8, IL-6, IL-10, TNF-α, and IL-1β may be potential diagnostic biomarkers for OC. Among them, TNF-α, IL-6, and IL-8 are highly accurate in the diagnosis of OC. Nevertheless, further studies that eliminate other confounding factors are warranted, and more standardized procedures and large-scale studies are needed to support the clinical use of saliva testing.

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Introduction

Oral cancer (OC) is one of the most frequent aggressive malignancies worldwide. It was estimated that there were 377,713 new OC cases (approximately 2% of all cancer cases) and 177,757 deaths (1.8% of all cancer-related deaths) in 2020 around the world [1]. This cancer may locally invade the tongue, lips, lower and upper gums, hard palate, retromolar trigone, and floor of the mouth, and even metastasize to distant sites at an advanced stage [2]. Squamous cell carcinoma (OSCC) represents approximately 90% of OC cases [3], and other OC types encompass salivary gland tumors, lymphomas, and sarcomas [4]. Due to asymptomatic characteristics, around 50% of individuals with OC are diagnosed at a late stage. Accordingly, the treatment of such patients is often aggressive and mutilating, adversely affecting their quality of life [5]. The 5-year relative survival rate is about 85.1% for localized OC, and is as low as 69.1% and 39.3% for lymphatic metastasis and distant metastasis, respectively [6]. Therefore, early diagnosis of OC is essential to reduce the mortality rate and ameliorate the quality of life of OC patients.

Currently, commonly-used diagnostic approaches for OC include traditional oral visual examination (VOE), classical biopsy followed by histopathological assessment, vital staining (such as toluidine blue), and radiographic imaging [7]. Among them, biopsy and histopathological examinations are still the standard procedures for the diagnosis of OC [8]. Besides, the analysis of body fluids, especially saliva, is a promising and potential alternative to biopsy for early OC detection since it is adjacent to cancer cells, readily available, non-invasive, and inexpensive [9]. Human saliva consists of cytokines, circulating cells, DNA and RNA molecules, and derivatives of tissue and extracellular vesicles (EVs) [10]. Cytokines, as key mediators of cell communication, can control complex and dynamic cell–cell interactions and regulate various cancer-related pathways in the tumor microenvironment [11]. In histiocytology, cytokines such as IL-6 and IL-8 that are important in pro-inflammatory and pro-angiogenic responses can be detected in cell lines, tissue specimens, and serum of patients with Head and Neck squamous cell carcinoma (HNSCC includes OSCC, pharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, nasal squamous cell carcinoma, paranasal sinuses squamous cell carcinoma etc. [12, 13]. Moreover, a large scale gene expression profiling assisted by laser capture microdissection and microarray analysis was carried out, identifying the expression of 2 cellular genes: interleukin (IL)6 and IL-8 which are uniquely associated with OSCC [14]. Besides, a direct link between oral inflammation and cancer invasion was established by showing that neutrophils increase OSCC invasion through a tumor necrosis factor (TNFα)-dependent mechanism [15]. According to many case–control studies and previous systematic reviews and meta-analyses, the average levels of salivary cytokines such as IL-6, IL-8, TNF-α, IL-1β, and IL-10 are significantly different between OSCC, oral potentially malignant disorders (OPMD), oral leukoplakia (OL) and control saliva. Previous studies also showed that IL-6 and IL-8 concentrations in saliva were associated with different stages of OSCC and the presence of cervical metastasis [6, 16, 17]. Taken together, these findings suggest that these salivary cytokines may be potential diagnostic biomarkers for OC.

Nevertheless, there is no consensus on which biomarkers have the best diagnostic value for OC. Network meta-analysis for diagnostic tests (NMA-DT) is a new analysis approach that allows simultaneously comparing multiple diagnostic tests, at multiple test thresholds [18]. This novel technique can lessen bias and enhance statistical accuracy in the comparison of the diagnostic performance of multiple tests by borrowing strength from indirect evidence [19]. Therefore, this network meta-analysis was implemented to evaluate and compare the accuracy of five common salivary cytokines (IL-8, IL-6, TNF-α, IL-1β, and IL-10) in diagnosing OC and to rank these diagnostic tests based on a superiority index.

Methods

Protocol and registration

This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Diagnostic Test Accuracy (PRISMA-DTA) Checklist (The prisma-DTA checklist is in the Supplementary Table S5) [20]. The study protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO; registration ID: CRD42023430533).

Inclusion and exclusion criteria

The following studies were included: (1) case–control studies on human subjects; (2) patients diagnosed with OC; (3) OC was confirmed pathologically; (4) the controls were healthy subjects without systemic diseases; (5) studies that reported at least one of the diagnostic sensitivity and specificity of IL-8, IL-6, IL-10, TNF-α, or IL-1β in OC patients compared to healthy controls with no systemic disease and the concentrations of these salivary biomarkers.

The exclusion criteria were as follows: (1) duplicate publications; (2) reviews, systematic reviews, meta-analyses; (3) conference summaries/abstracts, case reports, guidelines, letters to editors, editorials, study protocols, brief correspondences, animal experiments; (4) full texts unavailable; (5) outcome data unextractable; (6) non-English articles.

Literature search

As of 10 April 2023, two independent investigators (Lijun, Huang (L, H) and Mingsi, Deng (M, D)) extensively retrieved electronic databases, including PubMed, Embase, Web of Science, and Cochrane Library. No restrictions were imposed on study type, date/time, or publication status. Search terms encompassed “cytokine”, “saliva”, and “oral cancer” in combination with “interleukin” or “interferon”. The specific search strategy is delineated in Table S1. Besides, the reference lists of related studies and reviews were manually retrieved.

Study selection

All retrieved studies were imported into EndNote 20 to eliminate duplicate records. Two investigators (L, H and Fen, Luo (F, L)) independently checked the titles and abstracts to remove irrelevant articles. A full-text review was then conducted to select eligible studies. A third reviewer (M, D) was consulted to settle any disagreements that arose throughout the literature screening process.

Data extraction and quality assessment

Relevant data were independently extracted from included articles by two investigators, encompassing title, first author, publication year, country, study design, sample size, gender, patient age, the outcomes (levels of different cytokines in saliva, sensitivity and specificity, true positives (TP), false positives (FP), true negatives (TN) and false negatives (FN) in predicting OC). Dissents, if any, were settled by consulting a third investigator.

The Newcastle–Ottawa Scale (NOS) [21] was employed to evaluate the quality of the included articles. Two researchers (L, H and M, D) independently assessed 8 items in three domains: selection of case and control groups, comparability between groups, and exposure factors. Except for comparability, which has 2 points, each item in the remaining domains has 1 point. The total score ranges from 0 to 9 points. Studies rated 8 or higher were regarded as high quality, while those rated 4 or less were deemed to be of low quality. Meanwhile, studies with a score of 5–7 were considered to have a medium quality. The Quality Assessment on Diagnostic Accuracy Studies (QUADAS) 2 tool were used to assess the risk of bias [22], too. The risk of bias was assessed in four key domains including patient selection, index test(s), reference standard, and flow and timing. Concerns regarding applicability (patient selection, index test(s), and reference standard) were determined. The degree of bias and applicability were expressed as high, low, or unclear, in accordance with the guidance documents. The quality assessment was implemented independently by two researchers. Any dissents were resolved by a third researcher (F, L).

Statistical analyses

A traditional meta-analysis was carried out to pool data from studies comparing the levels of salivary IL-8, IL-6, IL-10, TNF-α, and IL-1β in OC patients and controls (non-OC). Standardized mean difference (SMD) with 95% confidence intervals (CIs) was used as the effect size. A p < 0.05 signals statistical significance. Forest plots were generated to visually present the results. The I2 statistic was utilized to examine heterogeneity among studies. I2 > 50% indicates statistically significant heterogeneity, and therefore, a random-effects model was applied for data analysis. Potential publication bias was determined by using a funnel plot and Egger’s test.

Furthermore, a network meta-analysis for diagnostic tests (NMA-DT) was conducted to delve into which saliva cytokine is the most accurate for predicting OC. NMA-DT enables us to concurrently compare several diagnostic tests of saliv a cytokines with the gold standard, at various thresholds [23]. The relative performance, sensitivity, and specificity of the index tests were assessed in relation to standard diagnostic method for OC, and these tests were ranked utilizing the diagnostic odds ratios (DORs) and superiority index (Table S2 in the Supplementary Materials explains all statistical terms). Higher DOR and superiority values indicate higher accuracy of tests in detecting diseases. This network meta-analysis was conducted using the R package “rstan” (version 4.1.3; R Foundation for Statistical Computing, Vienna, Austria). Analysis of Variance (ANOVA) model based on the Bayesian algorithm was applied to exhibit network meta-analysis among four systems by utilizing two independent binomial distributions to describe the true positive and true negative rates between OC and non-OC patients, meantime considering the correlation between sensitivity and specificity [24]. In order to improve accuracy and compare diagnostic assays one by one, calculations were repeated 7 times (model_code = model, chains = 2, iterations = 10,000, warmup = 5000, thin = 5), and then, league tables for relative comparations were drawn. Review manager version 5.4 was employed to calculate summary receiver operating characteristic curve (SROC) values.

Results

Study selection

Initially, 3075 articles were obtained from the database search. After removing 1082 duplicates, 1993 articles remained. After screening the titles and abstracts, 58 articles were potentially eligible. Based on a full-text review, 18 studies were further excluded, including 4 studies without healthy-control group, 8 studies without required experimental group, 4 studies without cytokines of interest, 1 study with no outcome of interest, and 1 commentary. Finally, 40 articles were included in the traditional meta-analysis and 12 articles in the network meta-analysis. The study selection process is delineated in Fig. 1.

Fig. 1
figure 1

PRISMA flow diagram for search and selection of eligible studies included in the network meta-analysis

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Study characteristics

The characteristics of the 40 included studies are presented in Table 1. These studies were published between 2004 and 2023. 19 studies were conducted in Asia [25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43], 11 studies in Europe [16, 44,45,46,47,48,49,50,51,52,53], and 10 studies in North America [54,55,56,57,58,59,60,61,62,63]. A total of 1280 patients with OC (most of the patients had OSCC) and 1254 healthy controls were included. The sample size of the included studies ranged from 9 to 100, with a mean age of 46 to 73 years. All the case–control studies enrolled both adult males and females. The enzyme-linked immunosorbent assay (ELISA) was the most often utilized detection method for determining the levels of salivary cytokines, followed by the Luminex-based immunoassay, the bead-based multiplex immunoassay, and the chemiluminescent enzyme immunoassay. For example, in the study by Piyarathne et al. [44], protein levels of ILs were quantified using a commercially available sandwich enzyme-linked immune-sorbent assay (ELISA), with pre-coated plates: E-EL-H0149, E-EL-H0102 and E-EL-H0048 kits (Elabscience; Wuhan, Hubei, China). In the study by Laliberté et al. [54], cytokines were analyzed according to the immunoassay protocol for the Millipore Human Cytokine/Chemokine Magnetic Bead Assay Panel (HCYTMAG-60K-PX30 by EMD Millipore, USA) and Luminex detection. In the study by Sato, J. et al. [42], IL-6 concentrations were measured using a highly sensitive chemiluminescent enzyme immunoassay (Fujirebio Inc., Tokyo, Japan).

Table 1 General characteristics of the included studies
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Ten studies reported salivary IL-1β concentrations [25, 35, 36, 44, 47, 53,54,55, 57, 60], 4 of which reported its sensitivity and specificity in the diagnosis of OC [25, 36, 44, 60]. 24 studies reported salivary IL-6 concentrations [16, 31, 33,34,35,36,37,38,39,40,41,42, 44,45,46, 49, 50, 52,53,54, 56, 58, 61, 63], 5 studies reported sensitivity and specificity [16, 36, 44, 46, 47]. 20 studies reported salivary IL-8 concentrations [16, 25, 29, 32, 34,35,36, 39, 44, 45, 47, 54,55,56,57,58,59,60,61, 63], 8 studies reported sensitivity and specificity [16, 25, 29, 36, 44, 55, 60, 62]. 15 studies reported salivary TNF-α concentrations [16, 26,27,28,29, 34, 36, 45, 48, 52,53,54, 58, 61, 63], 5 of which reported sensitivity and specificity [16, 27, 28, 36, 47]. 5 studies reported salivary IL-10 concentrations [36, 43, 48, 51, 54], but none of them investigated its sensitivity and specificity.

Quality assessment

The NOS scores are provided in Table 1. The quality assessment results revealed that 1 study [31] was of high quality and the other 39 studies were of medium quality. Besides, the mean score of all included studies was 6.5. Table S3 in the Supplementary Materials illustrates the thorough point-by-point evaluation. For the risk of bias and applicability of diagnostic accuracy studies, we considered the overall risk of bias to be relatively low, and all included studies generated only low concern in all aspects (details in the Supplementary Figure S1). To be specific, there was a high risk of bias in participant selection due to case–control designs and inappropriate exclusions, with unclear consecutive sample of patients enrolled in some studies. In the index test assessment, 2 [16, 44] out of 12 studies had a low risk of bias, 10 studies [25, 27,28,29, 36, 46, 47, 55, 60, 62] were judged to be unclear. Regarding reference standard tests, all studies had a low risk of bias. For the flow and timing aspects, all studies demonstrated a low risk of bias in statements regarding the interval time between the reference test and the index test.

Meta-analysis for comparing saliva cytokines between OC patients and healthy controls

IL-6, as the most extensively investigated cytokine, was reported in 24 studies [16, 31, 33,34,35,36,37,38,39,40, 42, 44,45,46, 49, 52,53,54, 56, 58, 61,62,63,64], including 708 OC cases and 652 controls. The meta-analysis suggested an obvious increase in salivary IL-6 levels in OC patients (SMD = 2.32, 95% CI (1.61, 3.03), p < 0.001). There was a high degree of heterogeneity (I2 = 95.8%, Fig. 2A). However, the sensitivity analysis did not find the source of heterogeneity (Supplementary Figure S2) Furthermore, subgroup analyses were conducted depending on patients’ age (> 60, ≤ 60, or not grouped), the assay kits used (ELISA, Luminex-based Multiplex immunoassay or chemiluminescent enzyme immunoassay), and the geographic locations among the included studies (Europe, north America, or Asia), and the results showed that patients’ age and the assay kits were the source of heterogeneity (> 60, I2 = 0%, ≤ 60, I2 = 90.7%; ELISA kit, I2 = 96.5%; the Luminex-based Multiplex kit and the chemiluminescent enzyme kit, I2 = 0%, details see Supplementary Table S4). Egger's test pointed to the evidence of publication bias across these 24 studies (p < 0.001).

Fig. 2
figure 2

Forest plot of the saliva cytokine levels in OSCC patients versus healthy controls A IL-6 levels B IL-8 levels

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The second most commonly studied cytokine was IL-8, which was investigated in 20 studies [16, 25, 29, 32, 34,35,36, 39, 44, 45, 54,55,56,57,58,59,60,61,62, 65] encompassing 691 OC patients and 750 controls. According to the pooled analysis (Fig. 2B), salivary IL-8 levels were found to be markedly increased in the OC population (SMD = 1.73, 95%CI [1.20, 2.26], p < 0.001). The heterogeneity between studies was significant (I2 = 93.8%). The exclusion of individual studies did not alter the analysis results (Supplementary Figure S2). The results of subgroup analyses indicated that the assay kits were the source of heterogeneity (ELISA kit, I2 = 94.9%; the Luminex-based Multiplex kit and the chemiluminescent enzyme kit, I2 = 0%, details see Supplementary Table S4). Egger's test revealed significant publication bias (p = 0.03).

The salivary TNF-α level (Fig. 3A) was discussed in 15 studies [16, 26, 27, 29, 34, 36, 45, 48, 52,53,54, 58, 61, 62, 65], covering 460 cases and 435 controls. The pooled analysis showed significantly elevated TNF-α levels in OSCC patients (SMD = 2.27, 95% CI (1.27, 3.26), p < 0.001). Heterogeneity was high (I2 = 96.3%). Sensitivity analysis suggested that the exclusion of each study did not alter the pooled effect size (Supplementary Figure S2). Subgroup analyses showed that participants’ age and the assay kits were the source of heterogeneity (> 60, I2 = 0%, ≤ 60, I2 = 91.2%; ELISA kit, I2 = 96.3%; the Luminex-based Multiplex kit, I2 = 0%, Supplementary Table S4). Egger's tests (p = 0.065) revealed no publication bias.

Fig. 3
figure 3

Forest plot of the salivary cytokine levels in OC patients versus healthy controls A TNF-α levels B IL-1βlevels C IL-10 levels

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IL-1β was evaluated in 10 studies [25, 35, 36, 44, 53,54,55, 57, 59, 60], including 381 OC cases and 392 controls. The meta-analysis found that OC patients exhibited a considerably higher IL-1β level in comparison to the healthy controls (SMD = 0.79, 95% CI (0.58, 1.00), p < 0.001, Fig. 3B). Heterogeneity was low (I2 = 47.1%). The funnel plot (Supplementary Figure S3) and the Egger’s test suggested no publication bias (p = 0.393).

IL-10 levels were reported in 5 included studies [36, 43, 48, 51, 54], involving 99 OC cases and 139 controls. Higher levels of IL-10 were noted in OC patients in comparison to the control group (SMD = 0.80, 95% CI (0.12, 1.48), p = 0.022, Fig. 3C). High heterogeneity was observed (I2 = 88%). The sensitivity analysis demonstrated that leaving out any one study did not have an impact on the pooled results (Supplementary Figure S2), while the assay kits and the geographic locations were the source of heterogeneity (ELISA kit, I2 = 92.0%; the Luminex-based Multiplex kit, I2 = 0%; Asia, I2 = 0%; Europe, I2 = 92.0%, Supplementary Table S4). Egger's test and the funnel plot (Supplementary Figure S3) indicated no publication bias (p = 0.231).

Diagnostic accuracy estimate

Since no studies have mentioned the sensitivity and specificity of IL-10 in the diagnosis of oral cancer only the remaining 4 kinds of saliva cytokines (i.e., IL-6, IL-8, TNF-α, and IL-1β) were included in this network meta-analysis. 12 studies [16, 25, 27,28,29, 36, 44, 46, 47, 55, 60, 62] provided their sensitivity and specificity, involving 1058 participants, of whom 574 (54.3%) were OC patients. Among the included studies, 5 studies [16, 36, 44, 46, 47] assessed the diagnostic accuracy of IL-6 for OC, with the sensitivity varying from 0.75 to 1.00 and specificity from 0.49 to 0.80 (Fig. 4). The pooled sensitivity and specificity of IL-6 were 0.75 (95% CI: 0.71, 0.81) and 0.86 (95%CI: 0.82, 0.90), respectively (Table 2). 8 studies [16, 25, 29, 36, 44, 55, 60, 62] assessed the diagnostic accuracy of IL-8 for OSCC, with the sensitivity varying from 0.67 to 0.97, and specificity from 0.58 to 0.97 (Fig. 4). The pooled sensitivity and specificity of IL-8 were 0.80 (95%CI: 0.77, 0.83) and 0.80 (95%CI: 0.77, 0.84), respectively (Table 2). 5 studies [16, 27, 28, 36, 47] assessed the diagnostic accuracy of TNF-α for OC, with the sensitivity varying from 0.83 to 1.00, and specificity from 0.49 to 1.00 (Fig. 4). The pooled sensitivity and specificity of TNF-α were 0.79 (95%CI: 0.76, 0.84) and 0.92 (95%CI: 0.90, 0.95) (Table 2), respectively. 4 studies [25, 36, 60, 65] assessed the diagnostic accuracy of IL-1β for OC, with the sensitivity varying from 0.61 to 0.74, and specificity from 0.76 to 0.84 (Fig. 4). The pooled sensitivity and specificity of IL-1β were 0.66 (95%CI: 0.61, 0.72) and 0.75 (95%CI: 0.70, 0.81), respectively (Table 2).

Fig. 4
figure 4

Forest plots for the diagnostic accuracy of saliva cytokines. TP true positive, FP false positive, FN false negative, TN true negative, CI confidence interval

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Table 2 The sensitivity and specificity of saliva cytokines
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The network plot for the diagnostic accuracy of salivary cytokines for OC is illustrated in Fig. 5A. The NMA suggested that TNF-α ranked first, with the highest DOR (72.42, 95%CI: 34.00, 89.45), the second highest sensitivity (0.79, 95%CI: 0.76, 0.84), highest specificity (0.97, 95%CI: 0.69, 1.00), and the highest superiority index (Table 2). IL-6 ranked second, and the pooled sensitivity, specificity and DOR of IL-6 were 0.75 (95% CI: 0.71, 0.81), 0.86 (95% CI: 0.82, 0.90) and 25.13 (95% CI:13.48, 31.77), respectively, followed by IL-8 (sensitivity: 0.80, 95% CI: 0.77,0.83; specificity: 0.80, 95% CI: 0.77, 0.84; DOR: 19.09, 95% CI: 12.71, 23.33) and IL-1β (sensitivity: 0.66, 95% CI: 0.61, 0.72; specificity: 0.75, 95% CI: 0.70, 0.81; DOR: 7.57, 95% CI: 4.22, 9.42). Summary ROC results are presented in Fig. 5B.

Fig. 5
figure 5

A Evidence network plot of diagnostic accuracy of saliva cytokines for OC B Summary ROC plot of saliva tests

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Discussion

A traditional meta-analysis was carried out based on all available evidence from 40 case–control studies to compare the levels of salivary IL-8, IL-6, IL-10, TNF-α, and IL-1β in OC patients versus controls. Our research indicated that OC patients exhibited considerably higher levels of salivary IL-8, IL-6, TNF-α, IL-1β and IL-10 than healthy controls. To our knowledge, this is the first network meta-analysis to delve into the diagnostic accuracy of these cytokines for OC. Our NMA found that IL-8 had the highest sensitivity (0.80), followed by TNF-α (0.79) and IL6 (0.75). TNF-α had the highest specificity (0.92), followed by IL6 (0.86) and IL8 (0.80). Overall, the DOR results indicated that TNF-α had the highest accuracy for the diagnosis of OC.

In the tumor microenvironment, there are a large number of cytokines, which inhibit tumor-specific immune response and promote the proliferation of tumor cells [66, 67], thus contributing to the tumorigenesis and progression of tumors. Our results suggested that OC patients exhibited considerably higher levels of salivary IL-8, IL-6, TNF-α, IL-1β and IL-10 in comparison to healthy controls, which were consistent with previous studies [17, 68]. Specifically, Rezaei's meta-analysis implied that levels of IL-6 and IL-8 in saliva were markedly elevated in OC patients [68]. The meta-analysis by Chiamulera demonstrated significantly higher levels of salivary IL-8, IL-6, TNF-α, IL-1β and IL-10 in OC patients [17]. It has been proposed that cytokines in oral chronic/acute inflammation recruit neutrophils to form a feedback loop with OC cells, resulting in a pro-tumor phenotype [15]. Our research further supports this finding, suggesting that these cytokines can be used as potential biomarkers for OC.

The main purpose of our study was to compare common saliva cytokines so as to identify the best cytokine for diagnosing OC. According to our results, TNF-α was the most accurate and ranked first with a specificity of 0.92 and a sensitivity of 0.79, and its DOR value was much higher than others. TNF-α, a member of the enormous TNF cytokine family, plays a key role in numerous physiological and pathological cellular processes, such as cell proliferation, differentiation, and death, regulation of immune response to various cells and molecules, local and vascular invasion of tumors, and destruction of the tumor vascular system [69]. In both in vitro and in vivo models, as well as in patients with OC, the upregulation of TNF-α has been shown to enhance cell proliferation, whereas its downregulation inhibits the proliferation and migration of tumors [70, 71]. Moreover, elevated TNF-α in the OC tumor microenvironment has been reported to facilitate invasion through two mechanisms: (i) it fosters the pro-inflammatory and pro-invasive phenotype of OC cells; (ii) it acts as a paracrine mediator to promote the recruitment and activation of inflammatory cells [15, 72]. Simultaneously, TNF-α gene polymorphisms are strongly associated with an elevated risk of oral pre-cancer [73]. Based on our results, TNF-α could be a preferred biomarker for the diagnosis of OSCC.

Furthermore, our NMA implied that IL-6 and IL-8 ranked second (sensitivity: 75%; specificity: 86%) and third (sensitivity: 80%; specificity: 77%), respectively, while IL-1β ranked last (sensitivity: 66%; specificity: 75%). The diagnostic performance of IL-10 was not analyzed because the included studies did not provide the specificity and sensitivity of IL-10 for the diagnosis of OC. Previous studies and the results of the present study have shown that the IL-6 level in saliva is significantly elevated in OC patients [17], and there is a statistical difference in the concentration of IL-6 between pre-cancer state and the normal population [31, 63]. The concentration of IL-6 in saliva may be used as a biological marker for the early diagnosis of OC. For instance, an elevated IL-6 concentration indicates a higher probability of local OC recurrence [31]. Moreover, IL-6, as a member of the IL-6 cytokine family, is involved in the recruitment of neutrophils and macrophages, which is related to the pathogenesis of chronic inflammatory diseases. It not only contributes to the tumorigenesis and rapid progression of tumors, but also promotes the metastasis and spread of aggressive cancer cells [74]. Hence, IL-6 may serve as a major contributor to the occurrence and development of OC. IL-8, as a member of the CXC chemokine family, is a pro-inflammatory chemokine produced by immune cells under inflammatory conditions [75]. In the tumor microenvironment, IL-8 can not only enhance tumor cell proliferation or transformation into a migratory or stromal phenotype but also foster tumor angiogenesis or recruit additional immunosuppressive cells to the tumor, thereby promoting tumor progression [76]. In addition, cancer cells secrete IL-8, thus up-regulating the expression of matrix metalloproteinase-7 (MMP-7), which also contributes to OSCC invasion [77].

IL-1β stimulates the tyrosine phosphorylation of epidermal growth factor receptor (EGFR) through the chemokine ligand 1-receptor 2(CXCL1-CXCR2) axis, and regulates EGFR signal to promote the proliferation of dysplasia oral mucosa keratinocyte (DOK) and OSCC cells. However, a significant decrease in tyrosine phosphorylation of EGFR and a sharp decrease in DOK cell proliferation were observed by transfecting CXCL1-targeted short hairpin RNA (shRNA) with lentivirus or by using CXCR2 antagonists [78]. Lee et al. (2015) also find that IL-1β can promote the proliferation of DOK and OSCC cells, enhance the angiogenesis ability and the expression of epithelial-mesenchymal transition (EMT)-related genes Snail and Slug, and down-regulate expression of cadherin E, thereby resulting in OCC invasion and metastasis [79]. It is worth noting that IL-1β can activate the nuclear factor-κB (NF-κB) pathway and foster the expression and secretion of IL-6 and IL-8. As a powerful pro-inflammatory cytokine, IL-1β has been widely demonstrated to be upregulated in ovarian, lung, and gastrointestinal cancers, which are often associated with poor prognosis [80]. IL-10 is a representative anti-inflammatory and immunosuppressive factor that promotes immune escape of tumor cells [81]. A previous study has shown that in most OC samples, the expression of IL-10 is higher in tumor cells and stromal cells than in controls [82]. Based on our research results, IL6, IL8 and IL1β could be used as biomarkers of OC and serve as auxiliary diagnostic methods. Nonetheless, further studies are needed to explore the specific role of these cytokines in OSCC and investigate their diagnostic accuracy.

Strength, limitations, and Inspiration for future research

First of all, saliva detection provides a low-cost method for early diagnosis of oral cancer due to its advantages of non-invasive, convenient collection, processing and storage. And because saliva is in constant contact with oral lesions, it may be superior to blood or other body fluids. In our study, we found that several salivary cytokines (salivary cytokines) have strong diagnostic ability in oral cancer diagnosis. This suggests that in future studies, we can perform multiple cytokine tests on these three cytokines.

However, the study still has several limitations. The heterogeneity of the included studies was significant, similar to a previous meta-analysis [17]. As a result, the operating procedures for saliva collection, storage, and cytokine quantification should be standardized in the future. Additionally, a multicenter study with a larger sample size is warranted to rule out possible bias. Future studies should also consider some lifestyle factors, such as smoking and drinking, which may also influence IL levels (between cases and controls), although their influence may be wakened upon the occurrence of cancer [44, 65]. Few studies provided data on the sensitivity and specificity of IL-10 in diagnosing OC, so no relevant NMA was conducted. Further studies are desired to provide a more accurate evaluation of IL-10 in the diagnosis of OC. Some included studies conducted subgroup analysis by the stages of OC [16, 36, 45], but the correlation between cancer stages and cytokines was not investigated in our analysis. Since the early diagnosis of OSCC is closely related to the clinical treatment and prognosis of patients, further research in this area is necessary.

Previous studies [6] observed that IL-8 and il-6 concentrations in OC patients were significantly higher than those in OPMD patients, and also significantly increased compared with healthy subjects. This suggests that the amount of the increase may distinguish between oral cancer and precancerous states, lichen planus, periodontitis, or other inflammatory and infectious diseases. We look forward to conducting more control studies in the future to compare oral cancer with potential oral malignancies, oral inflammatory diseases, and even systemic inflammatory states to further improve its specificity in the diagnosis of oral cancer.

In addition, many studies have demonstrated the effects of cytokines in the treatment of cancers [83,84,85,86], so these cytokines provide an insight into future clinical treatment of OC.

Conclusion

This study suggests that salivary cytokines can be used as potential biomarkers for early diagnosis of OC. Given its high diagnostic specificity and sensitivity, TNF-α is recommended, followed by IL-6 and IL-8. Notably, salivary cytokine levels may be affected by other factors, such as potential malignant states, chronic local inflammation, and autoimmune diseases. Therefore, it is necessary to further distinguish the diagnostic accuracy of these cytokines in different disease states and compare them with OC and different OC stages. At the same time, more standard operating procedures and large-scale multi-center studies are needed to reduce bias and heterogeneity. It is believed that the TNF-α, IL-6, and IL-8 saliva test is an affordable technique for early clinical diagnosis of OC, which can provide novel insights into the targeted therapy of OC.

Availability of data and materials

All data supporting the findings of this study are available within the paper and its Supplementary Materials.

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Acknowledgements

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Funding

1. Changsha Natural Science Foundation. (No: kq2208484).

2. Research Program Project of Hunan Provincial Health and Wellness Commission. (No: 202108030155).

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Authors and Affiliations

  1. Department of Orthodontics, Changsha Stomatological Hospital, Changsha Hunan, 410006, China

    Lijun Huang, Fen Luo, Mingsi Deng & Jie Zhang

  2. School of Stomatology, Hunan University of Traditional Chinese Medicine, Changsha Hunan, 410208, China

    Lijun Huang, Fen Luo, Mingsi Deng & Jie Zhang

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  1. Lijun Huang
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  2. Fen Luo
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  4. Jie Zhang
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Contributions

All authors contributed to the study conception and design. Lijun Huang: Conceptualization, Methodology, Software, Writing- Original draft, Data curation, Visualization were performed; Fen Luo: Investigation, Writing - Original Draft, Writing – Reviewing and Editing, Funding acquisition were performed; Mingsi Deng: Methodology, Software, Writing- Original draft were performed; Jie Zhang: Conceptualization, Supervision, Project administration, Funding acquisition were performed. All authors read and approved the final manuscript.

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Huang, L., Luo, F., Deng, M. et al. The relationship between salivary cytokines and oral cancer and their diagnostic capability for oral cancer: a systematic review and network meta-analysis. BMC Oral Health 24, 1044 (2024). https://doi.org/10.1186/s12903-024-04840-3

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BMC Oral Health

ISSN: 1472-6831

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