Abstract
Aims: To evaluate the potential role of interleukin-31 and interleukin-33 in diagnosis and prognosis from endometrial cancer. Methods: Tissue samples and clinical data were collected from 260 patients with endometrial cancer and 150 control patients with benign uterine diseases. Immunohistochemistry and ELISA testing quantified the expressions of interleukin-31 and interleukin-33 and their receptors. After surgery, all patients were followed up for an average of 56.3 months. Surgical effects were evaluated based on the patients’ symptoms and signs. A two-sided P value <0.05 was considered significant. Results: IL-31, IL-33 and their receptors were significantly accumulated with the progression of endometrial cancer, in comparison to the controls. Moreover, the expressions were correlated with clinical characteristics, including tumor stage, differentiation, and associated with patients’ disease-free survival. Conclusions: Limited data was available between the expressions of IL-31 and IL-33 and the receptors in patients with endometrial cancer. Our study findings suggested that the expressions of IL-31 and IL-33 might become possible biomarkers for the diagnosis and prediction in endometrial cancer.
Keywords: IL-31/IL-31R, IL-33/ST2, endometrial cancer, biomarkers
Introduction
Endometrial cancer, the tumor originating in the endometrium, is the most common gynecological cancer in developed countries, and its prevalence is increasing [1]. More than 61 880 new cases have been diagnosed, which led to 12 160 estimated deaths in America in 2018 [2]. Early detection and treatment are critical to improve the prognosis of patients with endometrial cancer. Abnormal uterine bleeding is the most frequent symptom of endometrial cancer. Only about 15% of endometrial cancer occurs in women without vaginal bleeding. Many other disorders can also lead to the same symptom [3-5]. Serum levels of some tumor markers elevated in only 20% to 30% of patients [3,6]. Some factors perhaps could be used as new markers.
Cytokines are important immuno-regulatory proteins that mediate the interaction between immune and non-immune cells, including interleukins, tumor necrosis factor, colony-stimulating factor, chemotactic cytokines, and transforming growth factors, playing a key role in controlling innate and adaptive immune responses [7,8].
Interleukins are produced by a variety of cells and can be used in a variety of cells. Since scientists originally thought that those cytokines were secreted by white blood cells and had physiological functions that regulated white blood cells, named Interleukin [9]. More follow-up studies reported that interleukins can also affect the proliferation, maturation, adhesion, and metastasis of many types of cells, including tumor cells [9,10].
Interleukin 31 (IL-31) is a novel cytokine originally isolated from activated human T cell and mouse testis, Dillon et al. (2004). The mature IL-31 molecule is a 141-amino acid helix containing 4 alpha helices and belonging the Interleukin-6 (IL-6) family, which is mainly secreted by CD4+ T cells, mast cells, and mononuclear/giant cells, such as phagocytes and dendritic cells (DCs) [11]. The functional receptor of IL-31R exists in three forms (GLMR, GPL, and I31RA) and is widely distributed in activated monocytes, macrophages, myeloid progenitor cells, epidermal keratinocytes, eosinophils, and epithelium cells and lymphocytes [12-14]. Previously studies have shown that IL-31R can transmit a variety of signals in different tissues, and induce a variety of biological behaviors, including promoting vascular endothelial growth factor overexpression and promoting T cell proliferation, regulating hematopoiesis, regulating cell migration and proliferation, and inflammatory factors and immune responses [15].
Interleukin-33 (IL-33) is a cytokine discovered by Schmitz et al. in 2005 and belongs to the IL-1 family. A mature IL-33 molecule consists of 270 amino acid residues and is mainly secreted by type 2 T cells, natural killer cells, giant cells, etc., and can be continuously expressed in endothelial cells and epithelial cells [14,16,17]. The receptor ST2 of IL-33 is a member of the IL-1 receptor family. Its gene is called T1, DER-4 or Fit-1, locateding on chromosome-2 in humans and encoded by the IL1RL1 gene [16].
At present, the research of IL-31/IL-31R and IL-33/ST2 in endometrial cancer is quite limited; the roles have not been fully understood. Based on our literature review, this is the first article concentrating on the expression and correlation of IL-31/IL-31R and IL-33/ST2 in patients with endometrial cancer.
Materials and methods
Patients and controls
Approval from the ethics committee of West China Second University Hospital, Sichuan University, China was obtained at the beginning of the project. Two hundred and sixty patients with endometrial cancer were recruited on admission to the hospital from January 2014 to January 2015. These patients were pathological diagnosed by curettage of uterus, and confirmed by two pathologists before surgery. Post-surgery, tumors were staged according to the 2009 criteria for adenocarcinoma of the endometrium, as defined by the International Federation of Gynecology and Obstetrics. The patients did not receive prior chemotherapy or radiation. Another 150 age-matched females, who underwent hysterectomy at the hospital due to benign uterine diseases, and without history of cancers, were recruited as healthy controls.
Fresh tissue collection
With obtaining written informed consent from all patients, in compliance with the Declaration of Helsinki, a fresh sample of 1 cm × 1 cm × 1 cm was collected during the operation, within 10 min after uterus excision, and was stored at -80°C until testing.
Sectioning of tissues
Endometrium tissues were collected during surgery, and sectioned at 4 um. Clinical and histological data were collected.
ELISA
The ELISA kits (Raybio Systems) specific for human IL-31 and human IL-33 were used to detect IL-31 and IL-33 levels of fresh tissue, respectively. The sensitivity limits of the ELISA kits were separate from 4.92 pg/mL to 1200 pg/mL (IL-31) and from 2.05 pg/mL to 500 pg/mL (IL-33). The intra-assay and inter-assay reproducibility of the ELISA kits were 9%, 11% (IL-31) and 8%, and 11% (IL-33).
Immunohistochemistry
As part of routine clinical practice, three samples of primary tissue per patient were randomly selected and assayed for IL-31R and IL-33R by immunohistochemistry using rabbit anti-human (Abcam, USA). Staining pattern, intensity, and distribution were assessed by light microscopy. The receptors were considered present if distinct brownish nuclear staining was observed. Stained mononuclear cells are reported as percentage of all immune cells in the field.
The immunohistochemical staining results included the Intensity Score (IS) and the Proportion Score (PS). The IS standard: negative (uncolored) 0 points, weak positive (light yellow) 1 point, medium positive (yellow) 2 points, and strong positive (brown) 3 points. The PS standard: 0 point of, 1 point of 1% proportion, 2 points of (1%, 10%) proportion, 3 points of (10%, 33%) proportion, 4 points of (34%, 66%) proportion, and 5 points of (67%, 100%) proportion. The final score of each slice is the sum of the IS and PS. The theoretical minimum score is 0, and maximum score is 8 [18].
Statistical analysis
Data were analyzed in SPSS version 22.0 (IBM Company, USA) and are reported as mean ± standard deviation (range). Categorical variables were compared between patients and controls by Chi-Squared test. After testing for normality of the raw data, the correlation between clinical factors and levels of IL-31 and IL-33 with the receptors were analyzed by independent-samples t-test. The correlation between the tumor markers and the interleukin levels was analyzed with Student’s t-test. A two-sided p value <0.05 was considered significant. Figures were generated in GraphPad Prism 5 (GraphPad Software Inc., USA).
Results
The comparable clinical characteristics of patients and controls were listed in Table 1.
Table 1.
Clinical characteristics of patients and controls
| Characteristics | Patients, n (%) | Controls, n (%) | P value |
|---|---|---|---|
| Sample size | 260 | 150 | |
| Mean age ± SD (range), years | 59.3±10.25 (30-78) | 57.22±8.89 (29-76) | 0.875 |
| BMI mean ± SD, kg/m2 | 21.33±2.06 | 21.72±2.21 | 0.901 |
| Family history of cancer | |||
| Yes | 82 (31.54%) | 48 (%) | 0.923 |
| No | 178 (68.46%) | 102 (%) | |
| Menopausal status | |||
| Premenopausal | 143 (55%) | 83 (55.33%) | 0.948 |
| Postmenopausal | 117 (45%) | 67 (44.67%) | |
| History of pregnancy | |||
| Yes | 218 (83.85%) | 127 (84.67%) | 0.827 |
| No | 42 (16.15%) | 23 (15.33%) | |
| Uterine bleeding | |||
| Yes | 206 (79.23%) | ||
| No | 54 (20.77%) | ||
| FIGO stage | |||
| I | 188 (72.31%) | 0 | |
| II | 41 (15.77%) | 0 | |
| III | 26 (10%) | 0 | |
| IV | 5 (1.92%) | 0 | |
| Differentiation Stage | |||
| G1 | 112 (43.08%) | 0 | |
| G2 | 94 (36.15%) | 0 | |
| G3 | 54 (20.77%) | 0 | |
| Histology | |||
| Adenocarcinoma | 260 (100%) | 0 | |
| Non-adenocarcinoma | 0 (0%) | 0 | |
IL-31 and IL-33 expressions in endometrial tissues
The tissue levels of IL-31 and IL-33 in tumor patients were more elevated than the counterparts in controls, P<0.001 (Table 2).
Table 2.
The tissue expressions of IL-31 and IL-33 in patients and controls (pg/ml)
| Interleukins | Patients | Controls | P Value |
|---|---|---|---|
| IL-31 | 175.80±39.03 | 57.93±25.08 | <0.001 |
| IL-33 | 101.31±51.14 | 44.74±24.41 | <0.001 |
Note: Data are expressed as mean ± standard deviation (range).
Furthermore, the expressions of IL-31 and IL-33 in endometrial adenocarcinoma tumor tissues increased with the degree of differentiations, and the P values were both <0.001, which was statistically significant (Table 3).
Table 3.
The expressions of IL-31 and IL-33 in patients with differentiations (pg/ml)
| Interleukins | G1 | G2 | G3 | P Value |
|---|---|---|---|---|
| IL-31 | 88.16±36.31 | 155.68±46.51 | 221.83±59.06 | <0.001 |
| IL-33 | 65.71±26.05 | 110.55±39.25 | 160.17±41.32 | <0.001 |
Note: Data are expressed as mean ± standard deviation (range).
The expressions of IL-31R in tissues
By immunohistochemistry, IL-31R protein was the least expressed in normal endometrial cells, and the highest expression was found in G3 endometrial adenocarcinoma cells. The average scores of the groups were as follows: control group: 2.1 points, tumor group: 4.9 points.
In the control group, the staining score <2.1 was divided into IL-31R weak expression group with 82 cases. The staining score ≥2.1 was divided into IL-31R strong expression group with 68 cases. The difference in staining scores between the four groups was statistically significant (P=0.021*).
In the tumor group, the staining score <6.1 was further divided into IL-31R weak expression group with 123 cases. The staining score ≥6.1 was divided into IL-31R strong expression group with 137 cases. We further conducted an intra-group stratification analysis of the disease group specimens: 3.4 points in the G1 group, 5.6 points in the G2 group, and 7.8 points in the G3 group (Figure 1).
Figure 1.
Immunohistochemical staining of IL-31R in cancer and normal tissues. A. Well-differentiated endometrial cancer. B. Moderately differentiated endometrial cancer. C. Poorly differentiated endometrial cancer. D. Normal endometrial tissue. According to the staining criteria, the average scores of the groups were as follows: 3.4 points in the high-differentiation group, 5.6 points in the moderately differentiated group, 7.8 points in the poorly differentiated group, and 2.1 points in the normal group. The difference was statistically significant (P=0.021*).
Combined with the case data of the study subjects, we found that in the patients’ group, the intensity of IL-31R staining expression was related to the presence of diabetes (P=0.032), clinical stage (P=0.004) and differentiation level of the patients (P=0.011). While, in the control group, the intensity of IL-31R staining expression was not significantly associated with clinical characteristics including menopause, obesity, diabetes, or hypertension status (Table 4).
Table 4.
Relationship between IL-31R expression and clinical features in patient group
| Character | Number (n=260) | IL-31R Expression | P Value | |
|---|---|---|---|---|
|
| ||||
| Weak (n=123) | Strong (n=137) | |||
| Menopausal Status | ||||
| Premenopausal | 117 | 52 | 65 | 0.403 |
| Postmenopausal | 143 | 71 | 72 | |
| BMI | ||||
| <28 | 156 | 64 | 92 | 0.013 |
| ≥28 | 104 | 59 | 45 | |
| Diabetes | ||||
| Yes | 51 | 31 | 20 | 0.032 |
| No | 209 | 92 | 117 | |
| Hypertension | ||||
| Yes | 77 | 39 | 38 | 0.484 |
| No | 183 | 84 | 99 | |
| FIGO stage | ||||
| I | 188 | 76 | 112 | 0.004 |
| II | 41 | 27 | 14 | |
| III | 26 | 16 | 10 | |
| IV | 5 | 4 | 1 | |
| Differentiation | ||||
| G1 | 112 | 41 | 71 | 0.011 |
| G2 | 94 | 52 | 42 | |
| G3 | 54 | 30 | 24 | |
The correlations between IL-31 and IL-31R
We further verified the distribution of IL-31 and IL-31R staining results in the control, G1, G2, and G3 groups, confirming that all data were in a normal distribution. Pearson correlation analysis was performed on the results of IL-31 and IL-31R staining in each group. The results showed that there was a positive correlation between IL-31 and IL-31R staining in each group (Figure 2).
Figure 2.
Correlation analysis of IL-31 and IL-31R expressions in controls and patients with different differentiation. According to the Shapiro-Wilk test, each group of data is in normal distribution. A. Control group, R2=0.47, P<0.01, 95% CI: (0.27, 0.59). B. G1 group, R2=0.57, P<0.01, 95% CI: (0.28, 0.48). C. G2 group, R2=0.64, P<0.01, 95% CI: (0.75, 0.89). D. G3 group, R2=0.3441, P<0.01, 95% CI: (0.38, 0.74).
The relationship between the expression of IL-31R and the prognosis of patients
In the IL-31R strong expression group, 11 patients lost follow-up, the average follow-up time of the rest was 54.04 months, and 19 patients suffered recurrence, with the earliest recurrence time of 7 months and 55 months of the latest. The median recurrence time was 28.95 months after surgery.
In the IL-31R weak expression group there were 14 patients lost follow-up and another 14 patients had recurrence. Among the rest of the patients, the average follow-up time was 57.1 months, the earliest recurrence time was 14 months, and the latest recurrence time was 52 months. The median recurrence time was 31.79 months.
After analyzing the free survival (FS) of 235 patients, the difference of FS between IL-31R weak and strong expression group was statistically significant (Figure 3).
Figure 3.
Relationship between IL-31 expression and prognosis in endometrial adenocarcinoma. The difference was statistically significant (P=0.034*).
The expressions of ST2 in tissues
By immunohistochemistry, ST2 protein was the lowest expressed in normal endometrial cells, and the highest expression was found in G3 endometrial adenocarcinoma cells. The average scores of the groups were as follows: control group: 2.7 points, tumor group: 5.2 points, the difference was statistically significant.
In the control group, the staining score <2.7 was divided into ST2 weak expression group, a total of 67 cases; the staining score ≥2.7 was divided into ST2 strong expression group with 83 cases.
In the tumor group, staining score <5.2 was divided into ST2 weak expression group, a total of 108 cases, the staining score ≥5.2 was divided into ST2 strong expression group with 152 cases. We further conducted an intra-group stratification analysis of disease group specimens: G1 group: 3.3 points, G2 group 4.9 points, and G3 group 6.5 points (Figure 4).
Figure 4.
The expression of ST2 in cancer and normal tissues. A. Highly differentiated endometrial cancer. B. Moderately differentiated endometrial cancer. C. Poorly differentiated endometrial cancer. D. Normal endometrial tissue. According to the staining criteria, the average scores of the groups were as follows: 3.3 in the highly differentiated group, 4.9 in the moderately differentiated group, 6.5 in the poorly differentiated group, and 2.1 in the normal group (P=0.009*).
Combined with the clinical data, we found that the intensity of ST2 staining expression was related to the presence of obesity (P=0.012), diabetes (P=0.013) tumor stage (P<0.001) and differentiation levels (P=0.017), and the difference was statistically significant (Table 5).
Table 5.
Relationship between ST2 expression and clinical features in patient group
| Character | Number (n=260) | ST2 Expression | P Value | |
|---|---|---|---|---|
|
| ||||
| Weak (n=108) | Strong (n=152) | |||
| Menopausal Status | ||||
| Premenopausal | 117 | 53 | 64 | 0.266 |
| Postmenopausal | 143 | 55 | 88 | |
| BMI | ||||
| <28 | 156 | 55 | 101 | 0.012 |
| ≥28 | 104 | 53 | 51 | |
| Diabetes | ||||
| Yes | 51 | 29 | 22 | 0.013 |
| No | 209 | 79 | 130 | |
| Hypertension | ||||
| Yes | 77 | 36 | 41 | 0.268 |
| No | 183 | 72 | 111 | |
| FIGO stage | ||||
| I | 188 | 81 | 107 | <0.001 |
| II | 41 | 19 | 22 | |
| III | 26 | 16 | 10 | |
| IV | 5 | 3 | 2 | |
| Differentiation | ||||
| G1 | 112 | 47 | 65 | 0.017 |
| G2 | 94 | 47 | 47 | |
| G3 | 54 | 14 | 40 | |
In the control group, combining with the case data of the study subjects, the intensity of ST2 staining expression was not significantly associated with whether the patient had menopause, obesity, presence of diabetes, or hypertension.
The correlations between IL-33 and ST2
We further verified the distribution of IL-33 and ST2 staining results in each group, and there was a positive correlation the staining in each group (Figure 5).
Figure 5.
Correlation analysis of IL-33 and ST2 expressions in controls and patients with different differentiations. According to the Shapiro-Wilk test, each group of data is in normal distribution. A. Control group, R2=0.51, P<0.01, 95% CI: (0.27, 0.59). B. G1 group, R2=0.36, P<0.01, 95% CI: (0.27, 0.45). C. G2 group, R2=0.53, P<0.01, 95% CI: (0.25, 0.37). D. G3 group, R2=0.4, P<0.01, 95% CI: (0.14, 0.29).
The relationship between the expression of ST2 and the prognosis of patients
Nine patients were lost follow-up in the ST2 strong expression group, the average follow-up time of the rest of the 99 patients was 54.3 months, and 18 patients had recurrence. The earliest recurrence time was 7 months and the latest recurrence time was 51 months after operation with the median recurrence time of 28.7 months.
In the ST2 weak expression group, 15 patients were lost, the average follow-up time of the rest of the 136 patients was 56.9 months, and 15 patients suffered recurrence. The earliest recurrence time was 14 months and the latest time was 55 months. The median recurrence time was 31.9 months postoperative.
After analyzing the free survival (FS) of 235 patients, the difference of FS between ST2 weak and strong expression group was statistically significant (Figure 6).
Figure 6.
Relationship between ST2 expression and prognosis in endometrial adenocarcinoma. The difference was statistically significant (P=0.041*).
Discussion
Previous literature reports that the occurrence and development of multiple solid tumors are closely related to IL-31/IL-31R and IL-33/ST2 pathways. Low concentration of IL-31/IL-31R can significantly inhibit the proliferation of intestinal epithelial cells. If the cell concentration is increased, IL-31/IL-31R will lose its inhibitory activity and even promote cell proliferation and cell migration. IL-31/IL-31R is highly expressed in patients with follicular lymphoma. Its expression level is closely related to the tumor progression and prognosis [16]. Further studies also claimed IL-31/IL-31R can activate AKT pathway, a classical cellular pathway associated with deep cell proliferation, suggesting that IL-31/IL-31R may have an activity that regulates cell proliferation [14-16].
IL-33 and ST2 were not detected in normal tissues, but high expression in malignant tissues, considering that IL-33 may promote metastasis, invasion and spread of ovarian cancer [19]. Jovanovic found that exogenous IL-33 can promote malignant mammary tumor growth and induce tumor lung and liver metastasis [20,21]. Similar situations were also found in epithelial squamous cell carcinoma and breast cancer. IL-33 plays an important role in tumorigenesis and progression through its receptor ST2 [22-24]. In gastric cancer, the level of IL-33 expression is closely related to the clinical features such as depth of invasion, tumor stage, and distant metastasis [25,26]. In lung cancer, with the disease progresses, the normal vascular endothelium gradually decreases and IL-33 increases [27,28]. In colorectal cancer, IL-33 can promote the growth and metastasis of colorectal cancer, and play an important role in the recruitment of CD4+ T cells and tumor immune escape [28]. In ovarian cancer, IL-33 has similar effects [19,29,30]. In mouse models of breast cancer, the expression level of IL-33 in primary and metastatic gradually increased with time. After artificial knockout of the gene of interleukin receptor, the model mouse primary solid tumor incidence slowed down significantly, delaying the growth of the tumor. The lung and liver metastasis were also significantly inhibited [21]. Thus, activated IL-31R/ST2 may trigger rapid tumor progression by inhibiting the immune function of T lymphocytes and NK cells [31].
Through our research, we found that the expression of IL-31 and its receptors IL-31R, IL-33 and its receptor ST2 were higher in the tumor patients than in the normal group. At the same time, the higher tumor differentiation level, the later the stage, the higher the expression levels of IL-31, IL-33 and their receptors.
Pearson correlation analysis further showed that there was a positive correlation between IL-31/IL-31R and IL-33/ST2 expression: the expression level of interleukin was increased, and the receptor level was also increased accordingly. Inter-group analysis also showed that the expression of IL-31/IL-31R and IL-33/ST2 increased with the increase of cell atypical and tumor differentiation level. The difference was statistically significant, indicating that it was related to the differentiation level.
Survival analysis showed that patients with strong IL-31/IL-31R and IL-33/ST2 expressions had a slightly worse prognosis than those with high expression, which is consistent with the situation reported in the previous literature.
Conclusion
Combining the above experimental results and a systematic review of previous literature, we believe that IL-31/IL-31R and IL-33/ST2 may be involved in the progression of endometrial adenocarcinoma in some way, and with the prognosis of patients. Thus, the potential regulation mechanism of IL-31/IL-31R and IL-33/ST2 in endometrial adenocarcinoma is worthy of further investigation.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 81572573).
Disclosure of conflict of interest
None.
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