Expression of CREG2 gene in colon adenocarcinoma and its relationship with the prognosis
10.3760/cma.j.cn115355-20240319-00125
- VernacularTitle:CREG2基因在结肠腺癌中的表达及其与预后的关系
- Author:
Jiaqi GAO
1
;
Huiyu LI
Author Information
1. 山西医科大学第三医院（山西白求恩医院 山西医学科学院 同济山西医院）普通外科，太原 030032
- Publication Type:Journal Article
- Keywords:
Colonic neoplasms;
Adenocarcinoma;
CREG2 protein, human;
Prognosis;
Computational biology;
Immunohistochemistry
- From:
Cancer Research and Clinic
2025;37(7):505-513
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the expression of cellular repressor of E1A-stimulated gene 2 (CREG2) in colon adenocarcinoma (COAD) and its relationship with prognosis and tumor immune microenvironment.Methods:CREG2 mRNA expression data and survival data of patients were collected from 23 pan-cancer cohorts including COAD in the University of California, Santa Cruz (UCSC) database. The difference of CREG2 mRNA expression levels in cancer tissues and paracancerous tissues was compared. Univariate Cox proportional risk model was used to analyze the correlation of high and low expressions of CREG2 mRNA in pan-cancer tissues with the overall survival (OS) of patients; taking the pathological results as the gold standard, the optimal cut-off value of CREG2 mRNA expression level in cancerous and paracancerous tissues obtained by receiver operating characteristic (ROC) curve was used to group the high and low expressions. Kaplan-Meier method was used to draw the OS curve of pan-cancer CREG2 mRNA high and low expression groups, and log-rank test was used for comparison between groups. The data of patients with complete clinical data of the COAD cohort were further extracted from the UCSC database. The distribution of patients with high and low CREG2 mRNA expressions stratified by different clinicopathological characteristics of different groups was compared. Kaplan-Meier method was used to analyze the OS of patients with high and low CREG2 mRNA expressions as well as the OS of patients stratified by different clinicopathological characteristics, and log-rank test was used for comparison between groups; multivariate Cox proportional risk model was used to screen the independent factors influencing the OS of COAD patients. The chips of cancer tissues and the corresponding paracancerous tissues from 58 COAD patients were collected for immunohistochemical staining. CREG2 protein expression level between the cancer tissues and paracancerous tissues was compared. The product of the proportion of positive cells and the staining intensity score was treated as the CREG2 protein expression level in the tissues; taking pathological results as the gold standard, the ROC curve was used to analyze the therapeutic efficacy of CREG2 protein level in judging cancer tissues and paracancerous tissues. Based on the tumor immune assessment resource (TIMER) database, Pearson function was used to analyze the correlation between the CREG2 mRNA expression and the degree of immune cell infiltration in COAD tissues. ESTIMATE algorithm was used to obtain each immune infiltration score, and the immune infiltration score was compared between the CREG2 mRNA high and low expression groups.Results:In the 23 pan-cancer cohorts of UCSC database, the CREG2 mRNA expression level in 17 cohort cancer tissues including COAD was higher than that in paracancerous tissues, and the CREG2 mRNA expression level in 3 cohort cancer tissues including glioma was lower than that in paracancerous tissues, and the differences were statistically significant (all P < 0.05). Univariate Cox regression analysis showed that the OS of patients with high CREG2 mRNA expression was worse than that in those with low CREG2 mRNA expression in 5 cohort cancer tissues including COAD (236 cases, HR = 1.13, 95% CI: 1.01-1.26, P = 0.030), and in glioma cohorts (553 cases, HR = 0.90, 95% CI: 0.85-0.95, P < 0.001), the OS of patients with low CREG2 mRNA expression was worse than that in those with high CREG2 mRNA expression. Kaplan-Meier analysis also showed that the OS of COAD, lung adenocarcinoma, renal papillary cell carcinoma, and hepatocellular carcinoma patients with high CREG2 mRNA expression was worse than that of those with low CREG2 mRNA expression, and the OS of glioma patients with high CREG2 mRNA expression was better than that of those with low CREG2 mRNA expression. In the UCSC database, CREG2 mRNA expression level in 222 COAD patients with complete clinical data was higher than that in paracancerous normal tissues. The proportion of patients with high CREG2 mRNA expression in mismatch repair deficient patients with COAD was higher than that in mismatch repair normal patients [87.2% (34/39) vs. 69.4% (127/183)], and the difference was statistically significant ( P = 0.024). There were no statistically significant differences in the proportion of patients with high CREG2 mRNA expression among patients stratified by age, gender and pathological stage (all P > 0.05). Kaplan-Meier analysis showed that patients with pathological stage Ⅲ-Ⅳ, stage T 4, lymph node metastasis, distant metastasis, and high CREG2 mRNA expression had poor OS, and the differences were statistically significant (all P < 0.05); and multivariate Cox regression analysis showed that distant metastasis ( HR = 3.61, 95% CI: 1.81-7.23, P < 0.01) and high CREG2 mRNA expression ( HR = 4.29, 95% CI: 1.69-10.93, P < 0.01) were independent risk factors for poor OS in COAD patients. The result of immunohistochemistry method detection of clinical samples showed that in cancer and paracancerous tissues, CREG2 protein was mainly expressed in the cytoplasm, and the expression level of CREG2 protein in COAD tissues was higher than that in corresponding paracancerous tissues (164±23 vs. 146±24, P < 0.001). ROC curve analysis showed that CREG2 protein expression in COAD tissues could be used to judge cancer and paracancerous tissues (the area under the curve = 0.720, 95% CI: 0.628-0.814, P < 0.001). The analysis of the data in TIMER database showed that CREG2 expression level in COAD tissues was correlated with infiltration levels of CD8 + T cells ( R = 0.158, P = 0.001), CD4 + T cells ( R = 0.125, P = 0.012), macrophages ( R = 0.202, P < 0.001), neutrophils ( R = 0.248, P < 0.001), and dentritic cells ( R = 0.265, P < 0.001). The matrix score and estimated score in the high CREG2 expression group were higher than those in the low expression group, and the differences were statistically significant (all P < 0.05). Conclusions:CREG2 gene is highly expressed in COAD tissues, and its high expression may be related to the poor prognosis of COAD patients. The microenvironment of COAD with high CREG2 expression has a higher abundance of stromal cells, and CREG2 may be involved in immune regulation and immune response.
