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ZAR1 knockdown promotes the differentiation of human neuroblastoma cells by suppression of MYCN expression

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Abstract

Although DNA hypermethylation at non-promoter region of the Zygote arrest 1 (ZAR1) gene has been observed in many types of tumor, including neuroblastoma (NB), the role of this gene in tumor development and/or progression is unclear. One reason is that knowledge about the function of ZAR1 protein is limited. Although it has been reported that ZAR1 plays a crucial role in early embryogenesis and may act as a transcriptional repressor for some transcripts, the detailed mechanism is still elusive. In the present study, we analyzed public data of NB patients and found that higher expression levels of ZAR1 were significantly associated with a shorter survival period. Consistent with this result, ZAR1-depleted NB cells showed well-differentiated phenotypes with elongated neurites and upregulated expression of TRKA and RET, which are markers for differentiated NB. Moreover, the expression level of MYCN protein was markedly suppressed in ZAR1-depleted NB cells. MYCN-depleted cells showed similar phenotypes to ZAR1-depleted cells. The present findings indicate that ZAR1 has oncogenic effects in NB by suppressing cell differentiation via regulation of MYCN expression.

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Acknowledgements

We thank Ms. A. Oguni for her excellent technical support and Ms. K. Tagata for her secretarial assistance. The present study was supported in part by JSPS KAKENHI Grant Number 20793772 to R.H.; MEXT-Supported Program for the Strategic Research Foundation at Private Universities (2011–2015) to N.F., H.N., M.S., T.K., and K.F.

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Authors and Affiliations

  1. Department of Pediatric Surgery, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi, Tokyo, 173-0032, Japan

    Yosuke Watanabe, Yoshiaki Ishizuka, Takayuki Hirano, Eri Nagasaki-Maeoka, Reina Hoshi, Shinsuke Yoshizawa, Shota Uekusa, Hiroyuki Kawashima, Kiminobu Sugito & Tsugumichi Koshinaga

  2. Department of Molecular Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Kenichi Shinohara

  3. Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Itabashi, Tokyo, 173-0032, Japan

    Noboru Fukuda

  4. Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba, 260-8717, Japan

    Hiroki Nagase

  5. Division of General Medicine, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi, Tokyo, 173-8610, Japan

    Masayoshi Soma & Kyoko Fujiwara

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  1. Yosuke Watanabe
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Correspondence to Tsugumichi Koshinaga or Kyoko Fujiwara.

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Watanabe, Y., Ishizuka, Y., Hirano, T. et al. ZAR1 knockdown promotes the differentiation of human neuroblastoma cells by suppression of MYCN expression. Med Oncol 34, 158 (2017). https://doi.org/10.1007/s12032-017-0999-x

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