CLIC1 overexpression is associated with poor prognosis in gallbladder cancer

Abstract

The chloride intracellular channel 1 (CLIC1) gene family is a recently identified class of Cl channel proteins. Although CLIC1 involvement is well established in some cancers such as gastric cancer and colon cancer, its expression pattern in gallbladder cancer (GBC) remains unknown. The aim of our study was to investigate the expression of CLIC1 in relation to progression and prognosis of GBC. Eight fresh gallbladder cancers paired with adjacent non-tumour tissues were quantified using real-time PCR and Western blot. Tissue samples from resected gallbladder cancer (n = 75) and cholelithiasis (n = 75) were evaluated for CLIC1 expression by immunohistochemical staining. Their expression was correlated with different clinicopathological parameters. CLIC1 expression was significantly higher (62.7 %) in gallbladder cancer than in cholelithiasis (21.3 %, p < 0.001). CLIC1 levels were associated with the histological grade, TNM stage and perineural invasion (p < 0.05), but not with patient age, sex, lymph node metastasis or gallbladder stones (p > 0.05). Univariate Kaplan-Meier analysis showed that a positive CLIC1 expression was associated with a decreased overall survival (p < 0.001). Multivariate Cox regression analysis showed that CLIC1 expression and histological grade were independent risk factors for overall survival. Therefore, the expression of CLIC1 is closely related to the progression of GBC and may be used as an effective marker for predicting the prognosis of this disease.

Chloride intracellular channel 1 regulates the antineoplastic effects of metformin in gallbladder cancer cells

“…Chloride intracellular channel 1 (CLIC1) is a membrane protein that has chloride ion channel activity. High levels of CLIC1 expression were associated with metastasis in gallbladder carcinoma . Therefore, we investigated how the PI3K‐Akt axis, the Bcl‐2 family of proteins and CLIC1 affect the underlying molecular mechanism of metformin‐induced inhibition of cell proliferation and promotion of apoptosis in NOZ and GBC‐SD cells.…”

“…High levels of CLIC1 expression were associated with metastasis in gallbladder carcinoma. (19,20) Therefore, we investigated how the PI3K-Akt axis, the Bcl-2 family of proteins and CLIC1 affect the underlying molecular mechanism of metformin-induced inhibition of cell proliferation and promotion of apoptosis in NOZ and GBC-SD cells. The expression levels of these proteins were measured by Western blot analysis after treating the cell lines with various concentrations of metformin for 48 h. As shown in Figure 3(a), upregulation of Bax and downregulation of p-Akt and Bcl-2 were induced by metformin in a dose-dependent manner.…”

“…CLIC1 protein levels are reportedly increased in multiple human cancers and have been proposed as a tumor marker . CLIC1 mRNA and protein levels were highly expressed in gallbladder cancer tissues compared with adjacent non‐tumor tissues and associated with poor prognosis . It has been reported that membrane proteins such as SPRY2 and OCT‐3 can affect the antineoplastic effects of metformin .…”

“…Chloride intracellular channel 1 (CLIC1), a member of the p64 family, acts as a plasma membrane chloride ion channel. We previously showed that the levels of CLIC1 are increased in human gallbladder metastasis and that elevated expression of CLIC1 can promote invasion and migration in gallbladder cancer cells . Thus, we sought to explore the role of CLIC1 in GBC cells treated with metformin.…”

The role of microRNAs in gallbladder cancer

“…Approximately 10,650 cases of GBC and other biliary cancers were diagnosed in the United States in 2014 (3). Despite advances in the treatment of GBC in recent years, the majority of patients eventually develop local recurrent or distant metastatic disease, which is associated with a poor prognosis and an overall 5-year survival rate of <10% (4)(5)(6)(7). Early diagnosis, which is crucial for long-term survival of GBC patients, unfortunately occurs only accidentally in patients undergoing cholecystectomy for gallstones or cholecystitis, while the majority of the patients present with advanced metastatic disease due to the absence of specific symptoms and efficient biomarkers (8)(9)(10)(11)(12).…”