miR-214 and hypoxia down-regulate Necl-2/CADM1 and enhance ErbB2/ErbB3 signaling

Authors

  • Kenji Momose,

    1. Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan
    2. Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan
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  • Akihiro Minami,

    1. Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan
    2. Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan
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  • Yohei Shimono,

    1. Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan
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  • Kiyohito Mizutani,

    1. Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan
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  • Kentaro Nobutani,

    1. Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan
    2. Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan
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  • Takeshi Azuma,

    1. Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan
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  • Yoshimi Takai

    Corresponding author
    • Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan
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  • Communicated by: Eisuke Nishida

Correspondence: ytakai@med.kobe-u.ac.jp

Abstract

Necl-2/CADM1 is down-regulated by the promoter hypermethylation and/or the loss of heterozygosity at chromosome 11q23.2 in many types of cancers and serves as a tumor suppressor by interacting in cis with ErbB3 and suppressing the ligand-induced ErbB2/ErbB3 signaling for cell movement and death. However, the incidence of these epigenetic and genetic abnormalities of Necl-2 is 30–60% in these cancers. We investigated here other mechanisms that down-regulate Necl-2. miR-214, that is frequently up-regulated in a variety of cancers, targeted the 3′UTR of the Necl-2 mRNA directly, suppressed the translation of Necl-2 and enhanced the ligand-induced ErbB2/ErbB3 signaling in human colon cancer Caco-2 cells. Hypoxia reduced the Necl-2 protein level in a manner independent of miR-214 or hypoxia-inducible factor-1α in Caco-2 cells. These results indicate that miR-214 and hypoxia are novel regulators that down-regulate Necl-2 and enhance ErbB2/ErbB3 signaling.

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