Expression and role of anion exchanger 1 in esophageal squamous cell carcinoma

Abstract

Recent studies have described important roles for the anion exchanger (AE) in epithelial carcinogenesis and tumor behavior. The objectives of the present study were to investigate the role of AE1 in the regulation of genes involved in tumor progression and the clinicopathological significance of its expression in esophageal squamous cell carcinoma (ESCC). An immunohistochemical analysis was performed on 61 primary tumor samples obtained from ESCC patients who underwent esophagectomy. AE1 was primarily located in the cell membranes or cytoplasm of carcinoma cells, and its distribution pattern was related to the histological degree of the differentiation of SCC or the pT category. Among patients with pT2-3 ESCC, the 5-year survival rate of patients with diffuse AE1 expression (40.2%) was significantly lower than that of patients with focal expression (74.0%). AE1 was strongly expressed in KYSE150 and TE8 human ESCC cells. The depletion of AE1 using siRNA inhibited cell proliferation, migration, and invasion and induced apoptosis. The results of the microarray analysis revealed that MAPK and Hedgehog signaling pathway-related genes, such as DHH, and GLI1, were down-regulated in AE1-depleted KYSE150 cells. In conclusions, the results of the present study suggest that the diffuse expression of AE1 is related to a worse prognosis in patients with advanced ESCC, and that it regulates tumor progression by affecting MAPK and Hedgehog signaling pathways. These results provide an insight into the role of AE1 as a mediator of and/or a biomarker for ESCC.

The Proposal of Molecular Mechanisms of Weak Organic Acids Intake-Induced Improvement of Insulin Resistance in Diabetes Mellitus via Elevation of Interstitial Fluid pH

“…Bodily and cellular functions are controlled by various factors including ions such as Na + , K + , Ca 2+ , Mg 2+ , Zn 2+ , and Cl − [ 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 ]. On the one hand, pH (−log[H + ]) is recognized as one of classical items considered to be already fully understood in roles and mechanisms of homeostasis.…”

Chloride intracellular channel 1 as a switch among tumor behaviors in human esophageal squamous cell carcinoma

“…We previously reported that several ion transporters are expressed in human ESCC and play crucial roles in multiple cell functions. For example, Na + /K + /2Cl - cotransporter 1 (NKCC1) regulates cell cycle progression [ 25 ], K-Cl cotransporter 3 (KCC3) regulates cell migration and invasion [ 26 ], anion exchanger 1 (AE1) functions as a regulator of proliferation, survival, migration, and invasion [ 27 ], Na + /H + exchanger 1 (NHE1) plays a suppressive role in proliferation, survival, migration, and invasion [ 28 ], and aquaporin 5 (AQP5) affects proliferation and cell survival [ 29 ]. The objectives of the present study were to investigate the role of CLIC1 in the proliferation, apoptosis, migration, and invasion of ESCC.…”

Anion exchanger 2 suppresses cellular movement and has prognostic significance in esophageal squamous cell carcinoma

“…Possibly, cancer cells may require hypoxia-inducible AE2 distribution. Several reports including our previous study demonstrated that the expression of hypoxia-inducible factors was elevated with the change of pH regulators, such as carbonic anhydrase (CA), suggesting that they become effective prognostic factors in microenvironment where the expression of hypoxia-inducible factors is increased [ 11 , 13 , 30 ]. Although this mechanism needs to be elucidated in more detail in further studies, our results suggest the important and specific roles of AE2 at the IF of cancer.…”

“…The development and maintenance of such a microenvironment are directly driven by pH regulators, such as the anion exchanger (AE), Na + /H + exchanger (NHE), monocarboxylate transporter (MCT), vacuolar H+-ATPase, and carbonic anhydrase (CA) [ 5 – 7 ]. We previously investigated the functions of ion transporters [ 8 , 9 ], water channels [ 10 ], and pHi regulators including AE1 [ 11 ], NHE1 [ 12 ], and CA12 [ 13 ] in esophageal squamous cell carcinoma (ESCC). Our findings suggested that these cellular physiological factors are effective biomarkers, and their regulation may produce novel strategies for future therapies for ESCC [ 4 ].…”