Prognostic significance of IL11RA and its methylation in lung adenocarcinoma

Introduction

According to the data of 36 cancers from 185 countries in the world, lung cancer is still the leading cause of cancer morbidity and mortality. There are about 2.48 million new cases and 1.81 million deaths every year (1). Over 40% of all malignant tumors in the lungs are lung adenocarcinoma (LUAD), which is the most frequent pathological type (2). For patients with early-stage LUAD, surgery is an effective treatment that ensures a good prognosis and a high quality of life (3). For those with locally advanced or advanced LUAD who are not eligible for surgery, treatment options include radiotherapy, chemotherapy, immunotherapy, and targeted therapy (4). Even with these therapeutic advancements, there has been little improvement in the 5-year survival rate of LUAD (5). Hence, it is of profound significance to identify new biomarkers for forecasting LUAD prognosis and underlying therapeutic targets.

Interleukin-11 receptor alpha (IL11RA), a specific receptor for interleukin-11 (IL-11), is differentially expressed in various malignancies, like stomach cancer, prostate cancer, breast cancer, endometrial carcinoma, osteosarcoma, melanoma, and colon cancer (6-9). Currently, IL11RA is identified as being related to tumor progression, cell proliferation, and differentiation, implying its potential involvement in the process of carcinogenesis (10,11). Interestingly, IL11RA is markedly decreased in LUAD (12). But it is unclear whether low expression of IL11RA acts as a tumor suppressor or pro-oncogenic effect in LUAD. One recent study demonstrated that IL11/IL11RA signaling pathways may contribute to the immunomodulatory properties (13). Higher levels of IL11RA expression enhanced immune cell infiltration and suppressed tumor growth (14). Nevertheless, the link between IL11RA and immune microenvironment in LUAD is not well comprehended. Hence, this research aimed to elucidate the differential expression, methylation, prognosis value and immune infiltration of IL11RA in LUAD. We present this article in accordance with the TRIPOD reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2362/rc).

Methods

Acquisition of patient data

According to our previous research (15), transcriptomic data from The Cancer Genome Atlas (TCGA), including 59 normal and 526 LUAD tissue samples, were sourced from the University of California Santa Cruz (UCSC) Xena website (http://xena.ucsc.edu/). The transcriptomic data comprising 59 normal and 513 LUAD subjects were included in subsequent analysis after eliminating duplicate samples. Additionally, the UCSC Xena website also provided DNA methylation data for 32 normal and 471 LUAD subjects. For the meta-analysis, expression and survival data were sourced from TCGA and Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) databases (16). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

The IL11RA expression analysis in LUAD

According to our previous research (17), we examined IL11RA expression across various cancer types using the University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) (http://ualcan.path.uab.edu/) (18), Gene Expression Profiling Interactive Analysis (GEPIA) (http://gepia.cancer-pku.cn/) (19) and ONCOMINE (https://www.oncomine.org/) (20) databases. as well as the TCGA and GEO databases. Paired t-test and unpaired t-test was employed to assess the differences in IL11RA expression between the groups. Moreover, IL11RA protein expression levels were evaluated through immunohistochemistry in the Human Protein Atlas (HPA) database (http://www.proteinatlas.org) (21). To explore the connection between IL11RA expression levels and clinicopathological characteristics, we excluded some missing data and performed chi-square tests. We also estimated the expression of IL11RA under diverse clinical pathological parameters by Student’s t-test or Kruskal-Wallis test (22).

The IL11RA methylation analysis in LUAD

The methylation level of IL11RA in LUAD was evaluated by UALCAN database. After excluding patients who survive <30 days, survival differences among groups with distinct methylation levels were evaluated using the Kaplan-Meier (KM) approach (23). Likewise, to explore the connection between the distinct methylation levels of IL11RA and clinicopathological characteristics, we excluded some missing data and performed chi-square tests.

The prognostic analysis of IL11RA in LUAD

The data retrieval entry of meta-analysis was as follows in GEO database: (lung OR pulmonary OR respiratory OR bronchi OR bronchioles OR alveoli OR pneumocytes OR (air way)) AND (cancer OR tumor OR carcinoma OR neoplasm OR malignant OR adenocarcinoma) AND (survival) (24). Two thousand nine hundred and sixty-four LUAD patients from TCGA and 22 GEO data set were included for meta-analysis (25-45). According to our previous research (46), the “survminer” and “survival” packages in R software were utilized to individually calculate the hazard ratio (HR) and 95% confidence intervals (CIs) for 23 datasets. Then, a meta-analysis was performed through “meta” packages in R software. Random effect model was selected based on I²>50% and P<0.05 (47). Additionally, we also created a prognostic nomogram model using “regplot” R packages in R software for LUAD patients based on IL11RA gene expression and clinicopathologic characteristics, like age, gender, stage, T stage, N stage and M stage.

Gene set enrichment analysis (GSEA)

To clarify the possible mechanism of IL11RA in LUAD, GSEA was performed in LUAD patients of TCGA datasets through “clusterProfiler” packages in R software according to our previous research (48). All samples were divided into high expression group and low expression group according to the median value of IL11RA expression.

The correlation analysis between IL11RA expression and immune infiltration in LUAD

To evaluate the relevance between IL11RA expression and immune infiltration in LUAD, according to our previous research (49,50), we firstly used the “Estimate” R package to calculate immune, stromal, and ESTIMATE scores. Afterward, the “Gene Set Variation Analysis (GSVA)” R package was used to execute single sample gene set enrichment analysis (ssGSEA) to better illustrate the connection between IL11RA expression and 28 types of tumor-infiltrating immune cells (51). Finally, Tumor Immune Estimation Resource (TIMER; https://cistrome.shinyapps.io/timer/) was utilized to assess the association of IL11RA expression with B cells in LUAD and the survival difference between the high and low B cell. Besides, TIMER was used to analyze the association between IL11RA expression and immune cell markers.

Statistical analysis

R software facilitated all the statistical computations. The link between IL11RA expression and its DNA methylation levels was examined using the Spearman method. P<0.05 was regarded to be statistically different. Gene sets were deemed statistically distinct if their adjust P value <0.05.

Results

The expression of IL11RA is diminished in LUAD

To appraise the IL11RA expression in diverse malignancies, we performed the expression analysis of IL11RA in pan-cancer through UALCAN database (Figure 1A). The results we obtained indicated that compared with that in the normal tissues, the IL11RA messenger RNA (mRNA) expression were considerably increased in only liver hepatocellular carcinoma, while it was markedly decreased in 15 other cancers compared to normal tissue, including LUAD. The pan-cancer analysis from ONCOMINE database also demonstrated that IL11RA expression is down-regulated in the majority of tumors (Figure 1B). There is an indication that IL11RA could function as a tumor suppressor gene. In order to further validate the distinct expression of IL11RA in normal and LUAD samples, we performed the expression analysis based on multiple databases. The findings revealed that the mRNA expression of IL11RA in LUAD tissues from GEPIA (Figure 1C), TCGA (Figure 1D), GSE75037 (Figure 1E) and GSE31210 (Figure 1F) databases were significantly reduced compared with normal tissue. Furthermore, representative images of immunohistochemistry results from HPA database showed that the staining intensity of IL11RA was moderate positivity in LUAD tissues, whereas strong positivity in normal samples (Figure 1G). The findings indicate that IL11RA may exert significant roles in the tumorigenesis of LUAD.

Figure 1 The expression of IL11RA is diminished in LUAD. (A,B) The expression level of IL11RA in different types of tumor from UALCAN (A) and ONCOMINE (B) databases. (C-G) IL11RA expression levels in LUAD and normal samples from GEPIA (C), TCGA (D), GSE75037 (E), GSE31210 (F) and HPA (https://www.proteinatlas.org/ENSG00000137070-IL11RA/tissue/lung#img; https://www.proteinatlas.org/ENSG00000137070-IL11RA/cancer/lung+cancer#img) (G) databases (bar =200 μm, staining: CAB032830). *, P<0.05. GEPIA, Gene Expression Profiling Interactive Analysis; HPA, Human Protein Atlas; IL11RA, interleukin-11 receptor alpha; LUAD, lung adenocarcinoma; TCGA, The Cancer Genome Atlas; TPM, transcripts per million; UALCAN, University of Alabama at Birmingham Cancer Data Analysis Portal.

Analysis of IL11RA methylation profile in LUAD patients

It is well established that hypermethylation results in gene silencing. Consequently, we speculate whether DNA hypermethylation leads to down-regulation of IL11RA expression in LUAD. According to the UALCAN database, DNA methylation levels of IL11RA was considerably elevated in LUAD samples relative to normal samples (Figure 2A). IL11RA mRNA expression levels were found to be negatively correlated with DNA methylation levels in the TCGA databases (Figure 2B). The hypermethylation of IL11RA implied inferior prognosis in LUAD (Figure 2C). Above results indicate that hypermethylation negatively regulates the IL11RA gene, leading to its reduced expression in LUAD. Furthermore, we also explored the link between IL11RA expression and 5 methylation sites in the promoter region of IL11RA, Figure 2D clearly showed the distribution of 5 methylation sites. The results of correlation analysis illustrated that IL11RA expression is negatively linked with 4 methylation sites (Figure 2E). It is especially intriguing that methylation sites cg21504624 (Figure 2F) and cg14609668 (Figure 2G) was inversely related to the expression of IL11RA in LUAD, and their hypermethylation was closely linked to unfavorable overall survival (Figure 2H,2I). The findings imply that the hypermethylation of IL11RA may lead to its downregulation in LUAD, contributing to a worse prognosis for subjects.

Figure 2 Analysis of IL11RA methylation profile in LUAD patients. (A) The methylation level of IL11RA in tumor and normal samples from UALCAN dataset. (B) The relevance between IL11RA expression and its methylation level. (C) Kaplan-Meier curves of IL11RA hypermethylation and IL11RA hypomethylation in LUAD. (D) The distribution of 5 methylation sites in the promoter region of IL11RA. (E) The relevance between IL11RA expression and 5 methylation sites. (F) cg21504624 was inversely related to the expression of IL11RA. (G) Kaplan-Meier curves of the hypermethylation and hypomethylation of cg21504624 methylation sites in LUAD. (H) cg14609668 was inversely related to the expression of IL11RA. (I) Kaplan-Meier curves of the hypermethylation and hypomethylation of cg14609668 methylation sites in LUAD. IL11RA, interleukin-11 receptor alpha; LUAD, lung adenocarcinoma; OS, overall survival; UALCAN, University of Alabama at Birmingham Cancer Data Analysis Portal.

The relevance between IL11RA expression or its methylation and clinical pathological parameters of LUAD

We next explored the relevance between IL11RA expression or its methylation and clinical pathological parameters from the TCGA-LUAD project using the chi-square test. Our findings suggested that the expression of IL11RA was tightly linked with gender (P=0.009), stage (P=4.38e−04), T stage (P=3.77e−05), N stage (P=0.003), cancer status (P=5.76e−04) and IL11RA methylation (P=9.64e−05), while the methylation level of IL11RA was tightly linked with stage (P=0.03), T stage (P=0.02), N stage (P=0.03), primary therapy outcome (P=0.007) and IL11RA mRNA expression (P=4.36e−05) (Table 1). Interestingly, further examination indicated a reduction in IL11RA expression as the stage (Figure 3A, P<0.001), T stage (Figure 3B, P<0.001), and N stage (Figure 3C, P<0.001) advances, whereas no noteworthy link between IL11RA expression and other clinicopathologic characteristics, like M stage (Figure 3D, P=0.68), age (Figure 3E, P=0.72) and gender (Figure 3F, P=0.17). Besides, those with tumors (a patient with LUAD still has a tumor in his body after treatment) (Figure 3G, P=0.003) or new tumor event (new tumor grows in a lung cancer patient after treatment) (Figure 3H, P=0.003) exhibited much lower levels of IL11RA expression.

Figure 3 Correlation between IL11RA expression and clinicopathological parameters of LUAD patients from TCGA database. Expression of IL11RA in different clinicopathological parameters, such as stage (A), T stage (B), N stage (C), M stage (D), age (E), gender (F), cancer status (G), and new tumor event (H). IL11RA, interleukin-11 receptor alpha; LUAD, lung adenocarcinoma; TCGA, The Cancer Genome Atlas.

Reduced IL11RA expression correlates with a negative prognosis in LUAD

To elucidate the relevance between IL11RA expression and prognosis in LUAD, a meta-analysis was performed based on TCGA and GEO databases. Two thousand nine hundred and sixty-four patients from 23 studies were incorporated into this meta-analysis (Table 2). Of these 23 studies, 18 had HR less than 1 and 5 had HR equal or greater than 1. The pooled hazard ratios for the correlation between differentially expressed IL11RA and overall survival was 0.72 (95% CI: 0.61–0.86) (Figure 4), which indicates that low IL11RA expression is linked with deteriorated overall survival in LUAD. Furthermore, a nomogram for prognosis was designed to enhance the accuracy of survival predictions for LUAD patients based on IL11RA gene expression and clinicopathologic characteristics, like age, gender, stage, T stage, N stage and M stage. The results indicated that IL11RA gene expression and stage had the largest impact on prognosis prediction (Figure 5A). Further calibration curves confirmed that the nomogram’s predictions aligned well with the actual survival probabilities observed at 1-, 3-, and 5-year (Figure 5B-5D).

Figure 4 Forest plots of combined analyses on the association of overall survival with IL11RA expression in LUAD. CI, confidence interval; HR, hazard ratio; IL11RA, interleukin-11 receptor alpha; LUAD, lung adenocarcinoma; TE, treatment effect; seTE, standard error of treatment effect; TCGA, The Cancer Genome Atlas.

Figure 5 Construction of a prognostic nomogram model based on clinicopathologic characteristics and the gene expression. (A) Prognostic nomogram model integrated with IL11RA expression, age, gender, stage, T stage, N stage and M stage. (B-D) calibration curves of 1-, 3-, and 5-year OS. IL11RA, interleukin-11 receptor alpha; OS, overall survival.

IL11RA is involved in immune infiltration in LUAD

To shed light on the underlying biological roles of IL11RA in LUAD, we carried out GSEA analysis. Interestingly, the results demonstrated that multiple significant pathways related to immune response were enriched in the IL11RA high expression group (Figure 6A-6L), such as activation of immune response (P.adjust<0.001), natural killer cell activation (P.adjust=0.02), macrophage activation (P.adjust=0.02), T cell activation (P.adjust<0.001), B cell activation (P.adjust=0.002) and so on, which suggests that IL11RA might be implicated in tumor immune infiltration.

Figure 6 Pathways related to immune response were enriched in LUAD. Multiple signaling pathways related to immune response were enriched in the IL11RA high expression group, such as activation of immune response (A), adaptive immune response (B), humoral immune response (C), dendritic cell antigen processing and presentation (D), natural killer cell activation (E), macrophage activation (F), T cell activation (G), T cell proliferation (H), B cell activation (I), B cell proliferation (J), B cell mediated immunity (K), and B cell receptor signaling pathway (L). LUAD, lung adenocarcinoma; NES, normalized enrichment score.

Next, we measured the immune, stromal, and ESTIMATE scores to evaluate the immune status in the high versus low IL11RA expression groups. The analysis revealed that the group with reduced IL11RA expression had lower scores for immune (P<0.001), stromal (P=0.03), and ESTIMATE (Figure 7A, P<0.001). Above results reveal that IL11RA mRNA expression might be positively correlated with tumor immune infiltration. Moreover, we also carried out ssGSEA analysis to better clarity and concise present the link between IL11RA expression and tumor-infiltrating immune cells. As shown in Figure 7B, 17 of 28 immune cells were notably under-expressed in low IL11RA expression groups, whereas 4 immune cells exhibited elevated expression in low IL11RA expression groups. Findings from the correlation analysis demonstrated that IL11RA mRNA expression were significantly positively related to 17 of 28 immune cells, negatively linked with 4 immune cells, and had no statistically significant correlation with 10 immune cells (Figure 7C). What is intriguing is that both our analysis and the TIMER database results demonstrated a positive relationship between IL11RA expression and B cell infiltration (Figure 7D-7F), and the survival analysis results demonstrated that patients with LUAD who showed higher B cell expression experienced longer survival according to the TIMER database (Figure 7G). Above results suggests that IL11RA low expression may exert cancer-promoting effect by influencing the immune cells infiltration in LUAD, especially B cell.

Figure 7 The relevance of IL11RA expression with immune infiltration level in LUAD. (A) The difference in ESTIMATE score, immune score and stromal score between high and low IL11RA expression groups in TCGA database. (B) Comparison of the infiltrating score of 28 kinds of immune cells in high or low IL11RA expression groups. (C) The relevance between IL11RA expression and 28 kinds of immune cells. (D,E) The expression of IL11RA was positively linked with activated B cell (D) and immature B cell (E). (F) The expression of IL11RA was positively correlated with B cell in TIMER database. (G) Survival curves of the high and low infiltrating levels of B cell in TIMER database. *, P<0.05; **, P<0.01; ***, P<0.001; ****, P<0.0001; ns, P>0.05. IL11RA, interleukin-11 receptor alpha; HR, hazard ratio; LUAD, lung adenocarcinoma; TCGA, The Cancer Genome Atlas; TIMER, Tumor Immune Estimation Resource.

Ultimately, we utilized the TIMER database to analyze the link between IL11RA expression and markers of immune cells. The study discovered that 44 out of 52 immune cell markers, or 84.62%, showed a notable connection with IL11RA expression. Of the 52 correlations, 76.92% were positive, totaling 40, and 7.69% were negative, totaling 4 (Table 3). Above findings reveal a significant relationship between IL11RA expression and most immune cell markers in LUAD.

Discussion

The occurrence and progression of malignant tumors are caused by the interaction and influence of numerous factors and genes (52,53). Research indicates a strong link between lung cancer progression and irregular gene expression (54). Hence, it is of great significance to explore the pathogenesis and prognosis of lung cancer at the gene level, and to find new molecular mechanisms and effective therapeutic targets for LUAD. In this research, we demonstrated that IL11RA is lowly expressed and negatively correlated with its methylation level in LUAD. The prognosis of patients with low expression of IL11RA is poor, and the mechanism may be related to the reduction of immune cell infiltration.

In cancer, IL11RA, as a cell surface receptor, has been discovered to act as a protein that is both secretory and bound to membranes (55). Research has previously indicated that IL11RA is strongly linked to the development of tumors (56). In many types of neoplasm tissues, the IL11RA gene showed aberrant expression. In this research, we clarified that IL11RA mRNA expression was markedly diminished in the majority of tumors, including LUAD. The result implies that IL11RA may act as a potential tumor suppressor gene. In addition, the significant reduction in mRNA and protein expression of IL11RA in LUAD was confirmed by several databases. This tendency of low expression of IL11RA in LUAD coincides with previous research (12), but some tumors, like those in the stomach and breast, show inconsistency (9,57). This discrepancy may be associated with small sample sizes of normal tissues or incongruent detection assays. Interestingly, wo also observed a reduction in IL11RA expression as the stage, T stage, and N stage advances, which indicates that IL11RA may play a significant role in the cancer development and progression of LUAD. Our result suggests that IL11RA could be considered a promising molecular target for LUAD therapy.

Then, we carried out a prognostic meta-analysis of 2,964 LUAD patients from 23 studies based on TCGA and GEO databases. Of these 23 studies, 18 had HR less than 1 and 5 had HR equal or greater than 1. However, the pooled hazard ratios for the correlation between differentially expressed IL11RA and overall survival was less than 1. The findings indicated that lower IL11RA expression correlated with poorer outcomes in LUAD. These findings effectively highlighted that IL11RA might be a viable prognostic biomarker for LUAD.

Abnormal DNA methylation plays a role in the development and advancement of LUAD (58). By modulating the expression of oncogenes and tumor suppressor genes, DNA methylation contributes to the onset and growth of tumors (59,60). Thus, we speculate whether the low expression of IL11RA in LUAD is associated with DNA methylation? In this research, there was an inverse relationship between IL11RA mRNA expression and its methylation in LUAD. Furthermore, the hypermethylation of IL11RA implied dismal overall survival in LUAD. This result indicates that IL11RA gene is inversely regulated by hypermethylation, resulting in its low expression in LUAD.

Another significant finding of the research was that IL11RA expression was linked with immune infiltration levels in LUAD. In lung cancer, the tumor microenvironment is mainly populated by T cells, with B cells, macrophages, dendritic cells, and natural killer cells also being significant (61). By facilitating the movement of immune cells near malignant tumors, immune activating factors contribute to anti-tumor activity (62). Research has demonstrated that IL11RA and its related signaling pathways can significantly alter the tumor microenvironment and immune responses (14). Our findings suggested that multiple significant pathways related to immune response were enriched in the IL11RA high expression group, and the group with reduced IL11RA expression had lower scores for immune, stromal, and ESTIMATE, and IL11RA expression was closely linked to diverse immune cells, including activated CD4⁺ T cells, activated B cells, activated dendritic cells, natural killer cells, activated CD8⁺ T cells and so on. Moreover, IL11RA expression is also significantly linked with majority of immune cell markers in LUAD. Studies predominantly indicate that dendritic cells aid in the activation of antitumor T lymphocytes (63,64), and cancer patients with elevated T cell and B cell levels had improved survival outcomes (65-67). Further analysis illustrated that IL11RA expression was positively associated with B cell infiltration and LUAD patients with higher expression of B cells presented a longer survival time. Taken together, these findings imply that IL11RA could aid in the recruitment of immune infiltrating cells and may be involved in modulating the immune response in the development of LUAD, which leads to a less favorable survival outcome for LUAD patients.

Conclusions

In conclusion, our study suggests that IL11RA gene is inversely regulated by hypermethylation, resulting in its low expression in LUAD and decreased IL11RA expression is positively related to dismal survival outcome. Our work highlights that IL11RA may be a viable prognostic biomarker and an innovative molecular therapeutic target for individuals with LUAD. Nevertheless, we initially investigated the biological function of IL11RA in LUAD by bioinformatics analysis. Additional biomedical experiments are required to clarify the concrete molecular mechanism that links low IL11RA expression to the progression of LUAD.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2362/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2362/prf

Funding: This investigation was supported by the Hunan Provincial Natural Science Foundation of China (No. 2021JJ40185 to Z.W./No. 2021JJ40503 to H.Y./No. 2023JJ40583 to G.H./No. 2023JJ40588 to Z.L./No. 2023JJ40591 to A.N.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2362/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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