Research Papers:

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

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

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Oncotarget. 2018; 9:25993-26006. https://doi.org/10.18632/oncotarget.25417

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Atsushi Shiozaki1,*, Shoichiro Hikami1,*, Daisuke Ichikawa1,2, Toshiyuki Kosuga1, Hiroki Shimizu1, Michihiro Kudou1, Yuzo Yamazato1, Toshiyuki Kobayashi1, Katsutoshi Shoda1, Tomohiro Arita1, Hirotaka Konishi1, Shuhei Komatsu1, Takeshi Kubota1, Hitoshi Fujiwara1, Kazuma Okamoto1, Mitsuo Kishimoto3, Eiichi Konishi3, Yoshinori Marunaka4,5 and Eigo Otsuji1

1Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan

2Department of Gastrointestinal, Breast and Endocrine Surgery, Faculty of Medicine, University of Yamanashi, Chuo 409-3898, Japan

3Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan

4Departments of Molecular Cell Physiology and Bio-Ionomics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan

5Japan Institute for Food Education and Health, St. Agnes’ University, Kyoto 602-8013, Japan

*These authors contributed equally to this work

Correspondence to:

Atsushi Shiozaki, email: shiozaki@koto.kpu-m.ac.jp

Keywords: AE2; esophageal squamous cell carcinoma; MMPs; migration; cellular physiology

Received: June 30, 2017     Accepted: April 28, 2018     Published: May 25, 2018


Background: Recent studies have reported essential roles for various intracellular pH regulators in epithelial carcinogenesis and tumor progression. The aims of the present study were to investigate the role of anion exchanger 2 (AE2) in the regulation of tumor progression-related genes and the prognostic value of its expression in esophageal squamous cell carcinoma (ESCC).

Results: AE2 was strongly expressed in KYSE170 and TE13 cells. The depletion of AE2 in these cells increased cell migration and inhibited the induction of apoptosis. The results of the microarray analysis revealed that various matrix metalloproteinase (MMP) signaling pathway-related genes, such as MMP1, MMP12, and TIMP4, were up- or down-regulated in AE2-depleted KYSE170 cells. Immunohistochemical staining showed that AE2 was primarily located in the cell membranes or cytoplasm of carcinoma cells, and its expression pattern at the invasive front of the tumor was related to the pT category. Prognostic analyses revealed that the low-grade expression of AE2 at the invasive front was associated with shorter postoperative survival.

Conclusions: The results of the present study suggest that reductions in AE2 in ESCC enhance cellular movement by activating MMP signaling pathways and are related to a poor prognosis in patients with ESCC.

Methods: In human ESCC cell lines, knockdown experiments were conducted using AE2 siRNA, and the effects on cellular movement and survival were analyzed. The gene expression profiles of cells were examined using a microarray analysis. An immunohistochemical analysis was performed on 61 primary tumor samples obtained from ESCC patients who underwent esophagectomy.

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