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

Shiozaki, Atsushi; Hikami, Shoichiro; Ichikawa, Daisuke; Kosuga, Toshiyuki; Shimizu, Hiroki; Kudou, Michihiro; Yamazato, Yuzo; Kobayashi, Toshiyuki; Shoda, Katsutoshi; Arita, Tomohiro; Konishi, Hirotaka; Komatsu, Shuhei; Kubota, Takeshi; Fujiwara, Hitoshi; Okamoto, Kazuma; Kishimoto, Mitsuo; Konishi, Eiichi; Marunaka, Yoshinori; Otsuji, Eigo

doi:10.18632/oncotarget.25417

Cited by 18 publications

(14 citation statements)

References 34 publications

(46 reference statements)

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“…Recent studies indicated that reductions in anion exchanger 2 (AE2) could activate MMP signaling pathways and enhance cellular movement in ESCC. Further analysis showed that AE2 was crucial to the poor prognosis of patients with ESCC [ 43 ]. Subsequently, Han et al found that MMP12 was closely related to nodal metastasis, tumor grade and staged poor survival of ESCC owing to its high expression in tumor cells [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of four genes and biological characteristics of esophageal squamous cell carcinoma by integrated bioinformatics analysis

Song

Wang

et al. 2021

Cancer Cell Int

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Background Esophageal squamous cell carcinoma (ESCC) has become one of the most serious diseases affecting populations worldwide and is the primary subtype of esophageal cancer (EC). However, the molecular mechanisms governing the development of ESCC have not been fully elucidated. Methods The robust rank aggregation method was performed to identify the differentially expressed genes (DEGs) in six datasets (GSE17351, GSE20347, GSE23400, GSE26886, GSE38129 and GSE77861) from the Gene Expression Omnibus (GEO). The Search Tool for the Retrieval of Interacting Genes (STRING) database was utilized to extract four hub genes from the protein–protein interaction (PPI) network. Module analysis and disease free survival analysis of the four hub genes were performed by Cytoscape and GEPIA. The expression of hub genes was analyzed by GEPIA and the Oncomine database and verified by real-time quantitative PCR (qRT-PCR). Results In total, 720 DEGs were identified in the present study; these genes consisted of 302 upregulated genes and 418 downregulated genes that were significantly enriched in the cellular component of the extracellular matrix part followed by the biological process of the cell cycle phase and nuclear division. The primary enriched pathways were hsa04110:Cell cycle and hsa03030:DNA replication. Four hub genes were screened out, namely, SPP1, MMP12, COL10A1 and COL5A2. These hub genes all exhibited notably increased expression in ESCC samples compared with normal samples, and ESCC patients with upregulation of all four hub genes exhibited worse disease free survival. Conclusions SPP1, MMP12, COL10A1 and COL5A2 may participate in the tumorigenesis of ESCC and demonstrate the potential to serve as molecular biomarkers in the early diagnosis of ESCC. This study may help to elucidate the molecular mechanisms governing ESCC and facilitate the selection of targets for early treatment and diagnosis.

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Section: Discussionmentioning

confidence: 99%

Identification of four genes and biological characteristics of esophageal squamous cell carcinoma by integrated bioinformatics analysis

Song

Wang

et al. 2021

Cancer Cell Int

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“…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.…”

Section: Variety Of the Interstitial Fluid Phmentioning

confidence: 99%

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

Marunaka

2018

IJMS

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Blood contains powerful pH-buffering molecules such as hemoglobin (Hb) and albumin, while interstitial fluids have little pH-buffering molecules. Thus, even under metabolic disorder conditions except severe cases, arterial blood pH is kept constant within the normal range (7.35~7.45), but the interstitial fluid pH under metabolic disorder conditions becomes lower than the normal level. Insulin resistance is one of the most important key factors in pathogenesis of diabetes mellitus, nevertheless the molecular mechanism of insulin resistance occurrence is still unclear. Our studies indicate that lowered interstitial fluid pH occurs in diabetes mellitus, causing insulin resistance via reduction of the binding affinity of insulin to its receptor. Therefore, the key point for improvement of insulin resistance occurring in diabetes mellitus is development of methods or techniques elevating the lowered interstitial fluid pH. Intake of weak organic acids is found to improve the insulin resistance by elevating the lowered interstitial fluid pH in diabetes mellitus. One of the molecular mechanisms of the pH elevation is that: (1) the carboxyl group (R-COO−) but not H+ composing weak organic acids in foods is absorbed into the body, and (2) the absorbed the carboxyl group (R-COO−) behaves as a pH buffer material, elevating the interstitial fluid pH. On the other hand, high salt intake has been suggested to cause diabetes mellitus; however, the molecular mechanism is unclear. A possible mechanism of high salt intake-caused diabetes mellitus is proposed from a viewpoint of regulation of the interstitial fluid pH: high salt intake lowers the interstitial fluid pH via high production of H+ associated with ATP synthesis required for the Na+,K+-ATPase to extrude the high leveled intracellular Na+ caused by high salt intake. This review article introduces the molecular mechanism causing the lowered interstitial fluid pH and insulin resistance in diabetes mellitus, the improvement of insulin resistance via intake of weak organic acid-containing foods, and a proposal mechanism of high salt intake-caused diabetes mellitus.

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“…Celay et al addressed the role of AE2 and its target peptide reduced tumor growth in vivo [30]. Enhanced AE2 promotes ovarian cancer progression by activating mTOR signaling [17]; whereas, reduction of AE2 enhances cellular migration via the activation of MMP pathways in the esophageal squamous cell carcinoma [31]. Despite the controversial effect of AE2 on tumorigenesis, as a drug repurposing, the attenuation of AE2 and its supportive enzyme CA12, and the inhibitory effect on cell migration by DSF in lung and breast cancer cells, provides evidence supporting the therapeutic potential of DSF against cancer as well as alcoholism.…”

Section: Discussionmentioning

confidence: 99%

Drug Repurposing as an Antitumor Agent: Disulfiram-Mediated Carbonic Anhydrase 12 and Anion Exchanger 2 Modulation to Inhibit Cancer Cell Migration

2019

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Disulfiram has been used in the treatment of alcoholism and exhibits an anti-tumor effect. However, the intracellular mechanism of anti-tumor activity of Disulfiram remains unclear. In this study, we focused on the modulatory role of Disulfiram via oncogenic factor carbonic anhydrase CA12 and its associated transporter anion exchanger AE2 in lung cancer cell line A549. The surface expression of CA12 and AE2 were decreased by Disulfiram treatment with a time-dependent manner. Disulfiram treatment did not alter the expression of Na+-bicarbonate cotransporters, nor did it affect autophagy regulation. The chloride bicarbonate exchanger activity of A549 cells was reduced by Disulfiram treatment in a time-dependent manner without change in the resting pH level. The expression and activity of AE2 and the expression of CA12 were also reduced by Disulfiram treatment in the breast cancer cell line. An invasion assay and cell migration assay revealed that Disulfiram attenuated the invasion and migration of A549 cells. In conclusion, the attenuation of AE2 and its supportive enzyme CA12, and the inhibitory effect on cell migration by Disulfiram treatment in cancer cells provided the molecular evidence supporting the potential of Disulfiram as an anticancer agent.

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

Cited by 18 publications

References 34 publications

Identification of four genes and biological characteristics of esophageal squamous cell carcinoma by integrated bioinformatics analysis

Identification of four genes and biological characteristics of esophageal squamous cell carcinoma by integrated bioinformatics analysis

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

Drug Repurposing as an Antitumor Agent: Disulfiram-Mediated Carbonic Anhydrase 12 and Anion Exchanger 2 Modulation to Inhibit Cancer Cell Migration

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