Abstract
Pathophysiological functions of chloride intracellular channel protein 3 (CLIC3) in human gastric cancer have been unclear. In the tissue microarray analysis using 107 gastric cancer specimens, CLIC3 expression was negatively correlated with pathological tumor depth, and the patients with lower expression of CLIC3 exhibited poorer prognosis. CLIC3 was expressed in the plasma membrane of cancer cells in the tissue. CLIC3 expression was also found in a human gastric cancer cell line (MKN7). In whole-cell patch-clamp recordings of the cells expressing CLIC3, NPPB-sensitive outwardly rectifying Cl− currents were observed. Cell proliferation was significantly accelerated by knockdown of CLIC3 in MKN7 cells. On the other hand, the proliferation was attenuated by exogenous CLIC3 expression in human gastric cancer cells (KATOIII and NUGC-4) in which endogenous CLIC3 expression is negligible. Our results suggest that CLIC3 functions as a Cl− channel in the plasma membrane of gastric cancer cells and that decreased expression of CLIC3 results in unfavorable prognosis of gastric cancer patients.
Highlights
Gastric cancer is one of the most common malignant tumors in the abdominal region [1, 2]
chloride intracellular channel protein 3 (CLIC3) was detected in MKN7 cells, while no significant signal of CLIC3 was observed in MKN74, MKN45, KATOIII, and NUGC-4 cells (Fig. 1d)
Corresponding to above results, Kaplan–Meier survival curves showed that expression level of CLIC3 was negatively correlated with overall survival (Fig. 2a) and disease-specific survival (Fig. 2b): that is, the CLIC3-low patients showed poorer survival rate compared to the CLIC3-high patients. These results suggest that decreased expression of CLIC3 in gastric cancer may result in poor prognosis of the patients
Summary
Gastric cancer is one of the most common malignant tumors in the abdominal region [1, 2]. The morbidity rate of gastric cancer has increased as the population ages [6]. Clarifying the mechanism of malignant traits is important to improve prognosis of gastric cancer. In gastric cancer, overexpression of several anion channels has been reported to be related to unfavorable prognosis of the patients: higher expression of chloride channel-3 (CLC-3) promotes cellular invasion in gastric cancer and predicts poor prognosis [7]. Overexpression of transmembrane protein 16A (TMEM16A), a Ca2+-activated Cl− channel, contributes to tumor invasion and poor prognosis of human gastric cancer [8]. Elevation of chloride intracellular channel 1 (CLIC1) is strongly correlated with lymph node metastasis, lymphatic invasion and pathological staging in gastric cancer [9]
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