The expression of Claudin 1 correlates with β-catenin and is a prognostic factor of poor outcome in gastric cancer

Abstract

Abstract. Claudin 1 is one of the tight junction proteins, which are critical in the maintenance of epithelial integrity. Aberrant regulation of CLDN1 and its correlation with β-catenin have been discovered in malignant tumors. The present study aimed to investigate the expression profile and clinical relevance of CLDN1 and β-catenin. The protein levels of CLDN1 and β-catenin were examined using immunohistochemical staining. The characteristics of expression profile and prognostic value were analyzed using Pearson's χ 2 test and Kaplan-Meier analysis, respectively. β-catenin overexpression and knockdown were used to investigate its role in regulating CLDN1 expression. We showed that CLDN1 was overexpressed in intestinal-type, presence of lymph node metastasis, higher TNM stage in gastric cancer patients and correlated with decreased overall survival. The characteristics of CLDN1 expression were associated with that of β-catenin. CLDN1 and β-catenin showed similar prognostic value in intestinal-type gastric cancers. β-catenin knockdown and overexpression in cell models revealed a positive relation between CLDN1 and β-catenin. Our study demonstrated that CLDN1 is a biomarker for intestinal-type gastric cancer with shorter survival. The expression of CLDN1 was strongly associated with β-catenin in gastric cancer patients and a gastric cancer cell model. IntroductionGastric cancer is the fourth most common cancer worldwide and is the second most common cause of cancer-related deaths.Gastric cancer has a poor prognosis (1). Although the 5-year survival rate in patients with early-stage disease is ~90%, since the vast majority present with distant metastasis, the overall 5-year survival rate is typically <20% (2). The 5-year survival rate has also been significantly correlated with the degree of tumor invasion, the presence of lymph node and/ or distant metastases and the TNM stage (3,4). However, very limited number of molecules that have clinicopathological significance in gastric cancer has been discovered.Claudin 1 (CLDN1) is one of the integral membrane proteins that constitute tight junctions. Tight junctions are essential for the tight sealing of cellular sheets and maintaining homeostasis (5). Absence of tight junctions or defective tight junctions is associated with the development of the neoplastic phenotype in epithelial cells (6). Thus it is accepted that the disruption of tight junctions leads to loss of cohesion, invasiveness and the lack of differentiation, thereby promoting tumorigenesis. CLDN1 is found to regulate intestinal epithelial homeostasis through the modulation of Notch-signaling (7). Many chemicals and nutrition can regulate CLDN1 expression through different pathways (8,9) to maintain the integrity of intestinal barrier function.The complexity of CLDN1 was proposed because its dual role as a tumor suppressor and promoter, as well as a positive and negative prognostic factor in different cancers, including breast (10,11), gastric (12), ovarian (13), lung (14) and colon (15-17). Decreased exp...

Down-Regulation of Claudin-1 Expression in Gastric Cancer Mucosa Is Correlated with Poor Prognosis

“…In contrast, Wu et al [14] reported that claudin-1 expression in invasive front was different from that in the mucosa of gastric cancer, and that the claudin-1 up-regulation in invasive front was positively related with the differentiated degree, and with the invasiveness and metastasis of gastric adenocarcinoma. Huang et al [26] showed that claudin-1 expression was increased in tumor tissues that were of intestinal type, differentiated type, at an advanced TNM stage and with lymph node metastasis. Their results are consistent with our findings which showed loss of claudin-1 in diffuse type gastric cancer.…”

Claudin-1, A Double-Edged Sword in Cancer

“…CLDN-1 is highly expressed in gastric cancers [108,109]. High expression of CLDN-1 was reported in intestinal type gastric cancer that correlated with lymph node metastasis, advanced TNM (classification of malignant tumors) stage, recruitment, and activation of MMP-2 and MMP-9, which are all responsible for enhanced cell invasion and metastasis [60,109].…”

“…CLDN-1 is highly expressed in gastric cancers [108,109]. High expression of CLDN-1 was reported in intestinal type gastric cancer that correlated with lymph node metastasis, advanced TNM (classification of malignant tumors) stage, recruitment, and activation of MMP-2 and MMP-9, which are all responsible for enhanced cell invasion and metastasis [60,109]. The invasion of gastric adenocarcinoma cells is associated with the levels of CLDN-1 expression as CLDN-1 is found to be upregulated in gastric carcinoma and participates in the metastatic behavior of these cancer cells [45].…”

Claudin-1 enhances tumor proliferation and metastasis by regulating cell anoikis in gastric cancer

“…For CLDN1, its overexpression in gastric cancer is related with tumor invasion and metastasis [ 15 , 16 ]. We recently reported that CLDN1 was highly expressed in intestinal-type gastric cancer and correlated with advanced TNM stage, lymph node metastasis and poor outcome [ 17 ]. However, the role and detailed mechanism of CLDN1 in gastric cancer are still unknown.…”

“…Integrity of cell-cell contacts prevents anoikis involving survival signal pathways activation of β-catenin, Src and PI3-K/Akt [ 23 , 28 ]. Indeed, there is a mutual interaction between CLDN1 and β-catenin [ 17 , 27 , 29 ]. The role of CLDN1 and β-catenin in the gastric tumorigenesis and metastasis piqued our interest in the further study.…”