Oncotarget

Research Papers:

PPP2R1A regulated by PAX3/FOXO1 fusion contributes to the acquisition of aggressive behavior in PAX3/FOXO1-positive alveolar rhabdomyosarcoma

Keisuke Akaike, Yoshiyuki Suehara _, Shinji Kohsaka, Takuo Hayashi, Yu Tanabe, Saiko Kazuno, Kenta Mukaihara, Midori Toda-Ishii, Taisei Kurihara, Youngji Kim, Taketo Okubo, Yasuhide Hayashi, Kazuya Takamochi, Fumiyuki Takahashi, Kazuo Kaneko, Marc Ladanyi and Tsuyoshi Saito

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Oncotarget. 2018; 9:25206-25215. https://doi.org/10.18632/oncotarget.25392

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Abstract

Keisuke Akaike1,2,*, Yoshiyuki Suehara1,*, Shinji Kohsaka3, Takuo Hayashi2, Yu Tanabe1, Saiko Kazuno4, Kenta Mukaihara1, Midori Toda-Ishii1, Taisei Kurihara1, Youngji Kim1, Taketo Okubo1, Yasuhide Hayashi5, Kazuya Takamochi6, Fumiyuki Takahashi7, Kazuo Kaneko2, Marc Ladanyi8 and Tsuyoshi Saito2

1Department of Orthopedic Surgery, Juntendo University School of Medicine, Tokyo, Japan

2Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan

3Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

4Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan

5Department of Hematology/Oncology, Gunma Children’s Medical Center, Shibukawa, Gunma, Japan

6Department of General Thoracic Surgery, Juntendo University School of Medicine, Tokyo, Japan

7Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan

8Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

*These authors contributed equally to this work

Correspondence to:

Yoshiyuki Suehara, email: ysuehara@juntendo.ac.jp

Tsuyoshi Saito, email: tysaitou@juntendo.ac.jp

Keywords: alveolar rhabdomyosarcoma (ARMS); proteomics; PAX3/FOXO1; PPP2R1A; PP2A

Received: January 30, 2018     Accepted: April 28, 2018     Published: May 18, 2018

ABSTRACT

To better characterize the oncogenic role of the PAX3-FOXO1 fusion protein in the acquisition of aggressive behavior in ARMS, we employed a proteomic approach using a PAX3-FOXO1 knockdown system in ARMS cell lines. This approach revealed a protein list consisting of 107 consistently upregulated and 114 consistently downregulated proteins that were expected to be regulated by PAX3-FOXO1 fusion protein. Furthermore, we identified 16 upregulated and 17 downregulated critical proteins based on a data-mining analysis. We also evaluated the function of PPP2R1A in ARMS cells. The PPP2R1A expression was upregulated at both the mRNA and protein levels by PAX3-FOXO1 silencing. The silencing of PPP2R1A significantly increased the cell growth of all four ARMS cells, suggesting that PPP2R1A still has a tumor suppressive function in ARMS cells; however, the native expression of PPP2R1A was low in the presence of PAX3-FOXO1. In addition, the activation of PP2A—part of which was encoded by PPP2R1A—by FTY720 treatment in ARMS cell lines inhibited cell growth. On the human phospho-kinase array analysis of 46 specific Ser/Thr or Tyr phosphorylation sites on 39 selected proteins, eNOS, AKT1/2/3, RSK1/2/3 and STAT3 phosphorylation were decreased by FTY-720 treatment. These findings suggest that PPP2R1A is a negatively regulated by PAX3-FOXO1 in ARMS. The activation of PP2A—probably in combination with kinase inhibitors—may represent a therapeutic target in ARMS. We believe that the protein expression profile associated with PAX3-FOXO1 would be valuable for discovering new therapeutic targets in ARMS.


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