Cellular physiological approach for treatment of gastric cancer

Recent studies show that ion channels/transporters play important roles in fundamental cellular functions that would be involved in the cancer process. We review the evidence for their expression and functioning in human gastric cancer(GC), and evaluate the potential of cellular physiological approach in clinical management. Various types of ion channels, such as voltage-gated K+ channels, intracellular Cl- channels and transient receptor potential channels have been found to express in GC cells and tissues, and to control cell cycles. With regard to water channels, aquaporin 3 and 5 play an important role in the progression of GC. Regulators of intracellular pH, such as anion exchanger, sodiumhydrogen exchanger, vacuolar H+-ATPases and carbonic anhydrases are also involved in tumorigenesis of GC. Their pharmacological manipulation and gene silencing affect cellular behaviours, suggesting their potential as therapeutic targets for GC. Our studies indicate theintracellular Cl- concentration could act as a mediator of cellular signaling and control cell cycle progression in GC cells. Further, we demonstrate the cytocidal effects of hypotonic shock on GC cells, and indicate that the blockade of Cl- channels/transporters enhances these effects by inhibiting regulatory volume decrease. A deeper understanding of molecular mechanisms may lead to the discovery of these cellular physiological approaches as a novel therapeutic strategy for GC.

Role of the Na^+/K^+/2Cl^- cotransporter NKCC1 in cell cycle progression in human esophageal squamous cell carcinoma

AIM:To investigate the role of Na+/K+/2Cl-cotransporter 1(NKCC1)in the regulation of genes involved in cell cycle progression and the clinicopathological significance of its expression in esophageal squamous cell carcinoma(ESCC).METHODS:An immunohistochemical analysis was performed on 68 primary tumor samples obtained from ESCC patients that underwent esophagectomy.NKCC1expression in human ESCC cell lines was analyzed by Western blotting.Knockdown experiments were conducted using NKCC1 small interfering RNA,and the effects on cell cycle progression were analyzed.The gene expression profiles of cells were analyzed by microarray analysis.RESULTS:Immunohistochemical staining showed that NKCC1 was primarily found in the cytoplasm of carcinoma cells and that its expression was related to the histological degree of differentiation of SCC.NKCC1 was highly expressed in KYSE170 cells.Depletion of NKCC1in these cells inhibited cell proliferation via G2/M phase arrest.Microarray analysis identified 2527 genes with altered expression levels in NKCC1depleted KYSE170.Pathway analysis showed that the top-ranked canonical pathway was the G2/M DNA damage checkpoint regulation pathway,which involves MAD2L1,DTL,BLM,CDC20,BRCA1,and E2F5.CONCLUSION:These results suggest that the expression of NKCC1 in ESCC may affect the G2/M checkpoint and may be related to the degree of histological differentiation of SCCs.We have provided a deeper understanding of the role of NKCC1 as a mediator and/or a biomarker in ESCC.