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PEG10 counteracts signaling pathways of TGF-β and BMP to regulate growth, motility and invasion of SW1353 chondrosarcoma cells

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Abstract

Recently, we reported highly active transforming growth factor (TGF)-β and bone morphogenetic protein (BMP) signaling in human chondrosarcoma samples and concurrent downregulation of paternally expressed gene 10 (PEG10). PEG10 expression was suppressed by TGF-β signaling, and PEG10 interfered with the TGF-β and BMP-SMAD pathways in chondrosarcoma cells. However, the roles of PEG10 in bone tumors, including chondrosarcoma, remain unknown. Here, we report that PEG10 promotes SW1353 chondrosarcoma cell growth by preventing TGF-β1-mediated suppression. In contrast, PEG10 knockdown augments the TGF-β1-induced motility of SW1353 cells. Individually, TGF-β1 and PEG10 siRNA increase AKT phosphorylation, whereas an AKT inhibitor, MK2206, mitigates the effect of PEG10 silencing on cell migration. SW1353 cell invasion was enhanced by BMP-6, which was further increased by PEG10 silencing. The effect of siPEG10 was suppressed by inhibitors of matrix metalloproteinase (MMP). BMP-6 induced expression of MMP-1, -3, and -13, and PEG10 lentivirus or PEG10 siRNA downregulated or further upregulated these MMPs, respectively. PEG10 siRNA increased BMP-6-induced phosphorylation of p38 MAPK and AKT, whereas the p38 inhibitor SB203580 and MK2206 diminished SW1353 cell invasion by PEG10 siRNA. SB203580 and MK2206 impeded the enhancing effect of PEG10 siRNA on the BMP-6-induced expression of MMP-1, -3, and -13. Our findings suggest dual functions for PEG10: accelerating cell growth by suppressing TGF-β signaling and inhibiting cell motility and invasion by interfering with TGF-β and BMP signaling via the AKT and p38 pathways, respectively. Thus, PEG10 might be a molecular target for suppressing the aggressive phenotypes of chondrosarcoma cells.

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Acknowledgements

This work was supported by grants from the Japan Society for the Promotion of Science (JSPS KAKENHI; 15K10486, 15K10410, 16K10910, 17K10972, 17K10933, 26462307, and 25462343) and The Vehicle Racing Commemorative Foundation. We gratefully acknowledge the technical assistance of Hui Gao. We thank Edanz Group (http://www.edanzediting.com/ac) for editing a draft of this manuscript.

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  1. Yuhei Yahiro and Shingo Maeda contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Joint Materials, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima, 890-8544, Japan

    Yuhei Yahiro, Shingo Maeda, Naohiro Shinohara, Go Jokoji, Daisuke Sakuma, Takao Setoguchi, Yasuhiro Ishidou, Setsuro Komiya & Noboru Taniguchi

  2. Department of Orthopaedic Surgery, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima, 890-8544, Japan

    Yuhei Yahiro, Naohiro Shinohara, Go Jokoji, Daisuke Sakuma, Satoshi Nagano, Setsuro Komiya & Noboru Taniguchi

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  1. Yuhei Yahiro
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Correspondence to Shingo Maeda.

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Yahiro, Y., Maeda, S., Shinohara, N. et al. PEG10 counteracts signaling pathways of TGF-β and BMP to regulate growth, motility and invasion of SW1353 chondrosarcoma cells. J Bone Miner Metab 37, 441–454 (2019). https://doi.org/10.1007/s00774-018-0946-8

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