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CAPS1 promotes colorectal cancer metastasis via Snail mediated epithelial mesenchymal transformation

Oncogene volume 38, pages 4574–4589 (2019)Cite this article

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Abstract

Colorectal cancer (CRC) is a common gastrointestinal cancer with high mortality rate mostly due to metastasis. Ca2+-dependent activator protein for secretion 1 (CAPS1) was originally identified as a soluble factor that reconstitutes Ca2+-dependent secretion. In this study, we discovered a novel role of CAPS1 in CRC metastasis. CAPS1 is frequently up-regulated in CRC tissues. Increased CAPS1 expression is associated with frequent metastasis and poor prognosis of CRC patients. Overexpression of CAPS1 promotes CRC cell migration and invasion in vitro, as well as liver metastasis in vivo, without affecting cell proliferation. CAPS1 induces epithelial–mesenchymal transition (EMT), including decreased E-cadherin and ZO-1, epithelial marker expression, and increased N-cadherin and Snail, mesenchymal marker expression. Snail knockdown reversed CAPS1-induced EMT, cell migration and invasion. This result indicates that Snail is required for CAPS1-mediated EMT process and metastasis in CRC. Furthermore, CAPS1 can bind with Septin2 and p85 (subunit of PI3K). LY294002 and wortmanin, PI3K/Akt inhibitors, can abolish CAPS1-induced increase of Akt/GSK3β activity, as well as increase of Snail protein level. Taken together, CAPS1 promotes colorectal cancer metastasis through PI3K/Akt/GSK3β/Snail signal pathway-mediated EMT process.

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Acknowledgements

We thank Dr. Hai-Ying Zeng from the Department of Pathology, Zhongshan Hospital of Fudan University, for technical assistance.

Funding

This work was supported by the National Natural Science Foundation of China (NSFC) (81672334, 81772615, 81572686, 81772968, 81573423, 81770137, 81672720) and Shanghai Science and Technology Commission (15410710100, 16ZR1406100).

Author contributions

SC, LD, XS, and GZ designed and conceived this project. GZ and SC developed methodology. GZ, YX, SW, and YC performed experiments and generated data. YX, SC, and SZ analyzed and interpreted data. YX, SC, and GZ wrote the manuscript. All authors contributed to and approved the manuscript.

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  1. These authors contributed equally: Guang-Xi Zhao, Ying-Ying Xu, Shu-Qiang Weng

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, 200032, China

    Guang-Xi Zhao, Shu-Qiang Weng, Xi-Zhong Shen & Ling Dong

  2. Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

    Guang-Xi Zhao, Ying-Ying Xu, Si Zhang & She Chen

  3. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

    Ying Chen

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Zhao, GX., Xu, YY., Weng, SQ. et al. CAPS1 promotes colorectal cancer metastasis via Snail mediated epithelial mesenchymal transformation. Oncogene 38, 4574–4589 (2019). https://doi.org/10.1038/s41388-019-0740-7

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