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KIAA1199 promotes metastasis of colorectal cancer cells via microtubule destabilization regulated by a PP2A/stathmin pathway

Oncogene volume 38, pages 935–949 (2019)Cite this article

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Abstract

Tumor metastasis is the main cause of death in advanced colorectal cancer. Our previous research showed that upregulation of KIAA1199 predicted poorer outcomes, and promoted cell motility and tumor metastasis in colorectal cancer, with the mechanisms not being fully elucidated. Here, we demonstrate that silencing of KIAA1199 results in reduced tumor metastasis in the orthotopic transplantation tumor model of colorectal cancer. Importantly, we find that KIAA1199 interacts with protein phosphatase 2A (PP2A) through the C-terminal domain and increases phosphatase activity of PP2A, which is essential for KIAA1199-mediated cell motility. Moreover, we identify stathmin, a microtubule-destabilizing protein, as a downstream of KIAA1199-PP2A complex. KIAA1199-induced dephosphorylation of stathmin results in microtubule destabilization and leads to enhanced cell motility. Furthermore, a microtubule-stabilizing drug paclitaxel could prevent KIAA1199-induced microtubule destabilization, and inhibit cell migration and invasion in vitro and tumor metastasis in vivo in colorectal cancer. Collectively, our study reveals that KIAA1199 promotes metastasis of colorectal cancer cells via microtubule destabilization regulated by a PP2A/stathmin pathway, and suggests that KIAA1199 may be a promising target for preventing metastasis in colorectal cancer.

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Acknowledgements

This work is supported by the National Natural Science Foundation of China (81702392 to LZ and 81874061 to TZ). The authors acknowledge Liang Zeng, Jingjing Wu, and Yan Xue for technical assistance, and thank Dr. Shuangbing Xu for critical review of the paper.

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  1. These authors contributed equally: Lei Zhao, Dejun Zhang, Qiong Shen

Authors and Affiliations

  1. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

    Lei Zhao, Dejun Zhang, Min Jin, Zhenyu Lin, Hong Ma, Gang Wu & Tao Zhang

  2. Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

    Qiong Shen

  3. Wuhan YZY Medical Science & Technology Co., Ltd., Wuhan 430075, China

    Shaoyi Huang & Pengfei Zhou

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Zhao, L., Zhang, D., Shen, Q. et al. KIAA1199 promotes metastasis of colorectal cancer cells via microtubule destabilization regulated by a PP2A/stathmin pathway. Oncogene 38, 935–949 (2019). https://doi.org/10.1038/s41388-018-0493-8

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