Diverse expression patterns of mucin 2 in colorectal cancer indicates its mechanism related to the intestinal mucosal barrier

Abstract

Background: Abnormal expression patterns of mucin 2 (MUC2) have been reported in a variety of malignant tumors and precancerous lesions. Reduced MUC2 expression in the intestinal mucosa, caused by various pathogenic factors, is related to mechanical dysfunction of the intestinal mucosa barrier and increased intestinal mucosal permeability. However, the relationship between MUC2 and the intestinal mucosal barrier in patients with colorectal cancer (CRC) is not clear.

Aim: To explore the relationship between MUC2 and intestinal mucosal barrier by characterizing the multiple expression patterns of MUC2 in CRC.

Methods: Immunohistochemical staining was performed on intestinal tissue specimens from 100 CRC patients, including both cancer tissues and adjacent normal tissues. Enzyme-linked immunosorbent assays were performed on preoperative sera from 66 CRC patients and 20 normal sera to detect the serum levels of MUC2, diamine oxide (DAO), and D-lactate (D-LAC). The relationship between MUC2 expression and clinical parameters was calculated by the χ ² test or Fisher's exact test. Prognostic value of MUC2 was evaluated by Kaplan-Meier curve and log-rank tests.

Results: Immunohistochemical staining of 100 CRC tissues showed that the expression of MUC2 in cancer tissues was lower than that in normal tissues (54% vs 79%, P < 0.05), and it was correlated with tumor-node-metastasis (TNM) stage and lymph node metastasis in CRC patients (P < 0.05). However, the serum level of MUC2 in CRC patients was higher than that in normal controls, and was positively associated with serum levels of human DAO (χ ² = 3.957, P < 0.05) and D-LAC (χ ² = 7.236, P < 0.05), which are the biomarkers of the functional status of the intestinal mucosal barrier. And the serum level of MUC2 was correlated with TNM stage, tumor type, and distant metastasis in CRC patients (P < 0.05). Kaplan-Meier curves showed that decreased MUC2 expression in CRC tissues predicted a poor survival.

Conclusion: MUC2 in tissues may play a protective role by participating in the intestinal mucosal barrier and can be used as an indicator to evaluate the prognosis of CRC patients.

Keywords: Colorectal cancer; Expression; Intestinal mucosal barrier; Mucin; Mucin 2; Prognosis.

Figure 1

Mucin 2 is mainly located in the cytoplasm. A: Normal tissue; B: Colorectal cancer tissue. Magnification: × 1000.

Figure 2

Representative pictures of immunohistochemical staining for mucin 2 in normal and cancer tissues of patients with colorectal cancer. A and B: Negative expression; C and D: Weak expression; E and F: Moderate expression; G and H: Strong expression. A, C, E, and G: Normal tissue; B, D, F, and H: Cancer tissue. Magnification: × 100 and × 400 (located in the upper right corner of each image).

Figure 3

Histogram of mucin 2 expression in cancer and normal tissues of patients with colorectal cancer. According to the comprehensive score of staining intensity and positive cell percentage, 0-3 was classified as low expression and 4-6 as high expression. ^aP < 0.05.

Figure 4

Comparison between the levels of serum diamine oxide, D-lactate, and mucin 2 in colorectal cancer patients and normal controls. A: The level of serum diamine oxidase in colorectal cancer (CRC) patients and normal controls (NC); B: The level of serum D-lactate in CRC patients and NC; C: The level of serum mucin 2 in CRC patients and NC. The numbers at the bottom of the bar chart represent the mean, and the numbers above the error line represent the standard deviation. ^cP < 0.001. CRC: Colorectal cancer; NC: Normal controls; DAO: Diamine oxidase; D-LAC: D-lactate; MUC2: Mucin 2.

Figure 5

Prognostic value of tissue mucin 2 expression in colorectal cancer patients. A: Correlation between tissue mucin 2 (MUC2) expression and disease-free survival in colorectal cancer (CRC) patients; B: Correlation between tissue MUC2 expression and overall survival in CRC patients; C: Histogram of the recurrence rate of CRC patients with different tissue levels of MUC2 expression. DFS: Disease-free survival; OS: Overall survival. MUC2: Mucin 2; CRC: Colorectal cancer.