Background
Thyroid carcinoma (THCA) is the most common endocrine malignancy worldwide [
1]. The incidence of THCA has increased sharply over the past 3 decades [
2]. Papillary thyroid carcinoma (PTC) is the major subtype of THCA, accounting for more than 90% of cases [
3]. The clinical course of PTC is generally indolent, and the cancer-specific mortality of PTC is low compared to that of other cancers [
4]. However, the incidence of cervical lymph node metastasis is high, which leads to local recurrence and poor prognosis [
5]. The main task for the future is to identify high-risk patients and to give them appropriate treatment and care [
6]. Therefore, further studies are required to explore the underlying mechanisms of tumorigenesis as well as identify additional biomarkers that predict prognosis and serve as therapeutic targets.
The interleukin-1 (IL-1) family of cytokines are the most effective molecules in the innate immune system [
7]. IL-1 receptor antagonist (IL1RN) was initially found as a natural antagonist of IL-1 [
8]. IL1RN is structurally related to IL-lα and IL-lβ but binds to IL-1 receptors on various target cells without inducing any discernible biological responses [
9]. The balance between IL1RN and IL-1 plays a crucial role in many diseases, including cancer [
10]. IL1RN has been studied in several cancers, including prostate carcinoma [
11,
12], cervical carcinoma [
13], gastric carcinoma [
14], bronchogenic carcinoma [
15], endometrial cancer [
16], lung cancer [
17], ovarian cancer [
18], oral malignancies [
19], leukemia [
20], and other cancers.
Two structural variants of IL1RN have been described: the soluble extracellular form (sIL-1ra) and the intracellular form (icIL-1ra) [
8]. Niedzwiecki, S. and colleagues assayed the serum levels of IL1RN in thyroid cancer patients. They measured preoperative IL1RN serum levels of patients with thyroid cancer, and the results showed that the serum concentrations of sIL-1ra were significantly higher in anaplastic carcinoma (ATC) and follicular carcinoma (FTC) patients [
21]. To our knowledge, no reports have been published to date concerning IL1RN expression in thyroid tissue. Because IL1RN has been associated with various diseases and the serum concentration of sIL-1ra has been confirmed to be increased in PTC, we hypothesized that IL1RN may play a role in PTC. The objective of this study was to investigate IL1RN expression in normal and PTC tissues by performing bioinformatics analysis to elucidate its possible role in tumor progression.
Discussion
In this study, we first revealed higher IL1RN expression in PTC tissue compared than in normal tissues and its diagnostic and prognostic value by integrated bioinformatics analysis. To further explore the potential function of IL1RN, we identified genes related to IL1RN expression, and functional enrichment analyses were conducted. The results of the KEGG pathway and GO analyses revealed the significant enrichment of genes in immune-related pathways. Our work further demonstrated that high IL1RN expression was significantly associated with decreased tumor purity and increased immune infiltration. Through methylation-related analysis, we determined that DNA methylation might be a regulatory mechanism of IL1RN. In addition, the analysis of the relationship between IL1RN expression and PTC mutations showed that high IL1RN expression was associated with mutated BRAF, wild-type NRAS and wild-type HRAS. Finally, IL1RN shows superior prognostic value for various cancers according to the pancancer analysis.
Niedzwiecki et al. [
21] revealed that the serum levels of IL1RN were upregulated in patients with ATC and PTC, but no statistically significant difference was found in PTC. We found that the expression of IL1RN was increased in PTC tissues compared with that in normal tissues in 1 TCGA cohort and 4 GEO cohorts and suggested that IL1RN might be used as a potential diagnostic biomarker in PTC. We guess that overexpression of IL1RN in thyroid tissues of PTC patients result in elevated levels of serum IL1RN. Thus, the findings of Niedzwiecki et al. corroborate our results. Our results were consistent with those of previous reports on the upregulation of IL1RN in cervical carcinoma [
13], gastric cancer [
14], lung cancer [
15], and endometrial cancer tissues [
16]. These findings are also basically consistent with the results of our pancancer study. In contrast to these findings, IL1RN exhibited low expression in oral squamous cell carcinomas (OSCCs) [
19].
The results of this study showed the value of IL1RN as a clinical biomarker in PTC and emphasized its potential as a prognostic biomarker in PTC patients. PTC patients with high IL1RN expression had decreased PFS compared to those with low IL1RN expression. Furthermore, high expression of IL1RN was significantly correlated with clinical stage, lymph node metastasis and pathological type. Various studies have highlighted the significant association between IL1RN expression and poor cancer prognosis; however, the results of these studies are conflicting. Some studies revealed that there was a significant positive correlation between poor prognosis and the expression of IL1RN [
14,
16,
28]. In contrast, low levels of IL1RN have been associated with increased disease severity in myeloma [
29], colorectal cancer [
30] and prostate cancer [
31].
The underlying mechanism of IL1RN in cancer development and progression is complicated and unclear. In this study, functional enrichment analysis of genes coexpressed with IL1RN showed that IL1RN participates in immune-related biological processes. Consistent with our findings, previous studies have focused on the role of IL1RN in tumor immunity. A study of gastric carcinoma [
14] pointed out that on the one hand, IL1RN may promote tumor growth via the impairment of cellular immunity; on the other hand, IL1RN enables malignant cells to escape host immune responses. Smith, D. R. et al. [
15] revealed that increased IL1RN in bronchogenic carcinoma is not accompanied by increased IL-1β activity. The altered balance of IL1RN and IL-1β may result in impaired immune surveillance and cytotoxic activity. An experimental study of human glioblastoma cells showed that IL1RN secreted by tumor cells can counteract IL-1 function, which represents a potential escape mechanism that supports cancer growth [
32]. In our study, IL1RN was significantly positively correlated with lymph node metastasis and tumor stage, so we speculated that IL1RN might also promote tumor aggressiveness and poor prognosis through immune-related mechanisms in PTC.
IL1RN is an endogenous natural antagonist of IL-1 [
8], so the discovery of the interaction between IL1RN and IL-1 family molecules is a breakthrough in exploring the function of IL1RN. Onozaki et al. [
33] reported that IL-1 is a cytocidal factor against several tumor cell lines. IL-1 may enhance cytotoxic T cell activity [
34], the tumoricidal capacities of natural killer (NK) cells [
35], and monocyte-mediated cytotoxicity [
36]. Because IL-1 is critical for tumor immunity, elevation of IL1RN expression may result in a general environment favourable to tumor cells and enhance the metastatic and recurrence potential of tumors by changing local IL-1-dependent pathways.
IL-1β has been reported as an anticancer factor that acts to suppress proliferation and reduce the invasive potential of human PTC cells [
37]. sIL-1ra has been shown to block IL-1 function by binding to IL-1 receptors at the cell membrane level [
34]. IcIL-1ra is postulated to inhibit intracellular IL-1 activity [
38]. Therefore, whether IL1RN can block the function of IL-1 and inhibit the anticancer effect of IL-1β in PTC is worth further study.
In our study, IL1RN showed a significant positive correlation with immune cells, which may be because a variety of immune cells can produce IL1RN through the stimulation of cytokines. Neutrophils produce IL1RN in response to granulocyte/macrophage colony stimulating factor (GM-CSF) and tumor necrosis factor-α (TNF-α) [
39]. IL-4 and IL-10 have been reported to increase the production of IL1RN by human monocytes [
36]. Yanagawa, H.et, al. reported that IL-13 increases IL1RN production by human alveolar macrophages [
40]. It was reported that the apoptotic cell death of monocytes was enhanced by administration of recombinant IL1RN [
41]. Our study also showed a significant correlation between IL1RN expression and various cytokines, which implied that IL1RN may play a complex role in tumor immunity.
Our study suggests that methylation is a pretranscriptional regulatory mechanism for IL1RN. The methylation level of IL1RN was negatively correlated with its expression level and was also correlated with the disease stage, lymph node metastasis, and pathological type.
IL1RN is likely to be a potential biomarker associated with the diagnosis and prognosis of PTC. However, although the diagnostic value, prognostic value and molecular functions of IL1RN in PTC have been analyzed through bioinformatics methods, the conclusions have not yet been confirmed by experiments. Therefore, further research is necessary to explore the role of IL1RN in PTC and the pharmacological value of IL1RN as a therapeutic target.
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