Cytokines are small molecular-weight regulatory proteins of the immune system that are secreted by active immune cells (mostly T cells, especially helper T (Th) cells). Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease susceptibility. The imbalance between pro- and anti-inflammatory cytokines may affect the inflammation-mediated oncogenesis. Inflammatory cytokines may play a pathogenic role in the development of oral precancerous lesions (OPL).1 Recently, we complete a pooled analysis of case–control studies regarding the association of polymorphisms in Th1/Th2-related cytokines with oral lichen planus (OLP) published in Journal of Dental Sciences.2 Although OLP is also classified as an oral potentially malignant disorder still with certain controversy, oral leukoplakia (OLK) and oral submucous fibrosis (OSF) are generally recognized as the typical OPL.
To consummate the relationship between polymorphisms in Th1/Th2-related cytokines and general oral potentially malignant disorders, we conducted a systematic literature search regarding this issue and identify case–control studies that included case of OPL (mainly OLK and OSF) and excluded OLP. As presented in Table 1, there were 8 eligible studies on polymorphisms in cytokines and OPL.3, 4, 5, 6, 7, 8, 9, 10 Since Chiu CJ and colleges reported the association between tumor necrosis factor-α (TNF-α) polymorphism and the risk of OSF as compared to betel quid chewers from Taiwan region, China,3 associations of several polymorphisms in cytokines with OPL were published with some inconsistent results. Therefore, this paper attempts to provide an adequate description and some pertinent comment on this issue.
Table 1.
Characteristics of the studies on polymorphisms in cytokines and oral precancerous lesions (OPL) risk.
| Author, year | Location | No. of cases | No. of controls | Cytokine | T-cell type pathway | SNP | Whether the SNP correlates with OPL risk |
|---|---|---|---|---|---|---|---|
| Chiu et al., 20013 | Taiwan | 166 OSF | 284 betel quid chewers | TNF-α | Th1 | 308G/A | Yes |
| Chiu et al., 20024 | Taiwan | 166 OSF | 284 betel quid chewers | TGF-β1 | Immunosuppressive | 509 C/T | Yes |
| Hsu et al., 20145 | Taiwan | 42 OPL | 128 HC | IL-6 | Th2 | 174G/C | Yes |
| IL-10 | Th2 | 1082 A/G, 819 T/C, 592 A/C | No | ||||
| TNF-α | Th1 | 308G/A | Yes | ||||
| TGF-β1 | Immunosuppressive | codon 10 T/C, codon 25 G/C | Yes | ||||
| IFN-γ | Th1 | 874T/A | No | ||||
| Rajendran et al., 20106 | India, Kerala | 50 OSF | 50 HC | TGF-β1 | Immunosuppressive | 509 C/T | Yes |
| Gupta et al., 20227 | India, Lucknow | 100 OLK, 200 OSF, 100 OLP, 100 OSCC | 500 HC | TNF-α | Th1 | 238G/A | No |
| TNF-β | Th1 | 252A/G | Yes | ||||
| Shahi et al., 20218 | India, Lucknow | 75 OPL, 75 OSCC | 100 HC | IL-6 | Th2 | 596G/A | Yes |
| 572G/C | Yes | ||||||
| Sharma et al., 20189 | India, Noida | 50 OPL, 100 OSCC | 150 HC | IL-10 | Th2 | 1082 A/G, 819 T/C, 592 A/C | Yes |
| Erdei et al., 201310 | Puerto Rico | 86 OPL, 62 OSCC | 155 benign lesions | TNF-α | Th1 | 238G/A | Yes |
| IL-1β | Th1 | 31C/T, 511A/G | No | ||||
| TGF-β1 | Immunosuppressive | 509 C/T | No | ||||
| IL-4 | Th2 | 524C/T | No | ||||
| IL-10 | Th2 | 3575 T/A, 1082 A/G, 819 T/C, 592 A/C | No |
HC, health control; OLK, oral leukoplakia; OLP, oral lichen planus; OSF, oral submucous fibrosis; SNP, single-nucleotide polymorphism.
For TNF-α polymorphism, both 2 studies from Taiwan region demonstrated the significant association of TNF-α (−308G/A) polymorphism with OPL susceptibility.4,6 In a Puerto Rican study,10 TNF-α (−238G/A) polymorphism was reported to be associated with the risk of OPL compare with benign oral lesions, but it was demonstrated to be associated with the risk of OLP but not OLK and OSF compare with health control in an Indian study.7 The other Th1-related cytokines, a study from Puerto Rico and Taiwan region reported that IL-1β (−31C/T, −511A/G) and IFN-γ (−874T/A) was not significantly associated with OPL susceptibility, respectively.5,10 For Th2-related cytokines, 2 studies from Taiwan region and India demonstrated the significant association of IL-6 (−596G/A, −572G/C, −174G/C) polymorphism with OPL susceptibility;5,8 While there was not association of IL-4 (−524C/T) polymorphism with OPL risk.10 Moreover, the results of IL-10 (−1082A/G, −819C/T, −592 A/C) and TGF-β1 (−509 C/T) polymorphisms associated with OPL susceptibility were inconclusive and inconsistent.5,10
The risk of OPL malignant progression is to develop into oral cancer. The meta-analyses demonstrated the significant associations of polymorphisms in TNF-α (not −238G/A but −308G/A), IL-10 (592A/C, 1082A/G), and TGF-β1 (not −509 C/T but −915G/C) with oral cancer susceptibility.11, 12, 13 Moreover, a recent meta-analysis reported no association between IL-6 (−174G/C) and IL-8 (−251A/T) polymorphisms and oral cancer risk.14 Meta-analysis allows stronger quantitative synthesis for identifying some models of risk markers, and reduces the limitations of the relatively small sample size and sampling bias of individual studies. Nevertheless, there existed some obvious limitations in OPL research. First, both the number (n ≤ 3) of eligible studies available and the sample size of each study are very small (Table 1). Secondly, the results are of heterogeneity due to role of various factors such as geographic distribution and ethnic differences on various predisposing factors involving lifestyle habits. Thirdly, the effect of the confounding ingredients in gene-environment exposures and lifestyle habits interactions such as environmental factors, and tobacco and alcohol use, were not assessed due to data not available. Hence, these limitations make narrowing down of synthesized results challenging and make the significance of meta-analysis less.
Herein, we also put forward a hypothesis whether polymorphism in a specific cytokine, e.g. TNF-α, correlates with the risk of OPL malignant progression to oral cancer. TNF-α as a pro-inflammatory multifunctional cytokine plays an important role in the regulation of immune response. TNF-α promotes cancer cell apoptosis and tumor-associated killing through the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling pathway.5 A G-to-A transition in the promoter region (−308) of the TNF-α gene results in its higher expression. We noted that TNF-α (−308G/A) polymorphism was associated with OPL and oral cancer susceptibility, respectively.5,11 Thus, one can hypothesize that it as an increased producer phenotype could be advantageous during oral carcinogenesis. Although associations of polymorphisms in cytokines with OPL and oral cancer were respectively examined in some studies,7, 8, 9, 10 the relationship between these polymorphisms and the risk of OPL progression compared to oral cancer was not analyzed.
Taken together, current evidence on the associations of polymorphism in Th1/Th2-related cytokines and genetic susceptibility towards OPL is not robust and should be interpreted prudently. Inflammatory cytokine coding genes responsible for immune response against disease susceptibility could be used as biomarkers in designing new theranostic strategies for OPL management in future. However, the impact of pro-inflammatory cytokines may vary and depends on both qualitative and quantitative factors: their concentration, expression duration, and their cell surface receptor expression levels being the essential determinants. Accordingly, further well-designed studies with larger sample size and multiple ethnicities are needed to validate these associations.
Declaration of competing interest
The authors have no conflicts of interest relevant to this article.
Acknowledgments
This work was supported by National Natural Science Foundation of China (82272831) and Innovative Research Team of High-Level Local Universities in Shanghai (SSMU-ZLCX20212300).
Contributor Information
Xi Yang, Email: yangxi015@tom.com.
Wei Liu, Email: liuweb@hotmail.com.
References
- 1.Yasasve M., Manjusha M., Saravanan M. Polymorphism in pro-inflammatory cytokines and their genetic susceptibility towards oral precancerous lesions and oral cancer. Oral Oncol. 2022;133 doi: 10.1016/j.oraloncology.2022.106027. [DOI] [PubMed] [Google Scholar]
- 2.Liu W., Li M., Zhang X., Zhou Z., Shen Z., Shen X. Association of polymorphisms in Th1/Th2-related cytokines (IFN-γ, TGFβ1, IL-1β, IL-2, IL-4, IL-18) with oral lichen planus: a pooled analysis of case-control studies. J Dent Sci. 2023;18:560–566. doi: 10.1016/j.jds.2022.08.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Chiu C.J., Chiang C.P., Chang M.L., et al. Association between genetic polymorphism of tumor necrosis factor-alpha and risk of oral submucous fibrosis, a pre-cancerous condition of oral cancer. J Dent Res. 2001;80:2055–2059. doi: 10.1177/00220345010800120601. [DOI] [PubMed] [Google Scholar]
- 4.Chiu C.J., Chang M.L., Chiang C.P., et al. Interaction of collagen-related genes and susceptibility to betel quid-induced oral submucous fibrosis. Cancer Epidemiol Biomarkers Prev. 2002;11:646–653. [PubMed] [Google Scholar]
- 5.Hsu H.J., Yang Y.H., Shieh T.Y., et al. Role of cytokine gene (interferon-γ, transforming growth factor-β1, tumor necrosis factor-α, interleukin-6, and interleukin-10) polymorphisms in the risk of oral precancerous lesions in Taiwanese. Kaohsiung J Med Sci. 2014;30:551–558. doi: 10.1016/j.kjms.2014.09.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Rajendran R., Harish R.K., Anil S., Vidyadharan R., Banerjee M. Transforming growth factor-β-1 polymorphisms are infrequent but exist at selected loci in oral submucous fibrosis. Indian J Dent Res. 2010;21:413–419. doi: 10.4103/0970-9290.70815. [DOI] [PubMed] [Google Scholar]
- 7.Gupta S., Nigam K., Srivastav R.K., Ahmad M.K., Mahdi A.A., Sanyal S. Genetic polymorphism of tumor necrosis factor alpha (TNF-α) and tumor necrosis factor beta (TNF-β) genes and risk of oral pre-cancer and cancer in North Indian population. Oral Maxillofac Surg. 2022;26:33–43. doi: 10.1007/s10006-020-00929-5. [DOI] [PubMed] [Google Scholar]
- 8.Shahi Y., Mukherjee S., Samadi F.M. Interaction of tobacco chewing and smoking habit with interleukin 6 promoter polymorphism in oral precancerous lesions and oral cancer. Eur Arch Oto-Rhino-Laryngol. 2021;278:4011–4019. doi: 10.1007/s00405-021-06620-z. [DOI] [PubMed] [Google Scholar]
- 9.Sharma U., Singhal P., Bandil K., et al. Genetic variations of IL-10: identification of novel variations and evaluation of the impact of the SNPs/haplotype in the promoter region with the progression of Oral Squamous Cell Carcinoma in Indian population. Cytokine. 2018;103:99–108. doi: 10.1016/j.cyto.2017.09.016. [DOI] [PubMed] [Google Scholar]
- 10.Erdei E., Luo L., Sheng H., et al. Cytokines and tumor metastasis gene variants in oral cancer and precancer in Puerto Rico. PLoS One. 2013;8 doi: 10.1371/journal.pone.0079187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Gao X., Ma L., Sun H., Jian X. Association between two common polymorphisms of TNF-α gene (-308 and -238) and the risk of head and neck carcinomas based on case-control studies. Int J Clin Exp Med. 2016;9:2738–2747. [Google Scholar]
- 12.Qu Y., Feng J., Wang L., et al. Association between head and neck cancers and polymorphisms 869T/C, 509C/T, and 915G/C of the transforming growth factor-β1 gene: a meta-analysis of case-control studies. Med Sci Mon Int Med J Exp Clin Res. 2019;25:8389–8402. doi: 10.12659/MSM.917506. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Li Y.F., Yang P.Z., Li H.F. Functional polymorphisms in the IL-10 gene with susceptibility to esophageal, nasopharyngeal, and oral cancers. Cancer Biomarkers. 2016;16:641–651. doi: 10.3233/CBM-160606. [DOI] [PubMed] [Google Scholar]
- 14.Rezaei F., Mohammadi H., Heydari M., et al. Association between IL-8 (-251T/A) and IL-6 (-174G/C) polymorphisms and oral cancer susceptibility: a systematic review and meta-analysis. Medicina (Kaunas) 2021;57:405. doi: 10.3390/medicina57050405. [DOI] [PMC free article] [PubMed] [Google Scholar]