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LASP1 interacts with N-WASP to activate the Arp2/3 complex and facilitate colorectal cancer metastasis by increasing tumour budding and worsening the pattern of invasion

Oncogene volume 39, pages 5743–5755 (2020)Cite this article

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Abstract

LIM and SH3 protein 1 (LASP1) is a metastasis-related protein reported to enhance tumour progression in colorectal cancer (CRC). However, the underlying mechanism is still elusive. As the major biological and pathological functions of LASP1 are accomplished by its LIM and SH3 domains via protein–protein interactions, a yeast two-hybrid system was employed to screen novel LASP1-interacting proteins. N-WASP, a member of the Wiskott–Aldrich syndrome protein (WASP) family, was screened and identified as a LASP1-interacting protein overexpressed in CRC tissues. N-WASP could stimulate the migration and invasion of CRC cells in vitro and increase the formation of subcutaneous tumours, mesenteric implanted tumours and hepatic metastatic tumours. N-WASP could interact with and activate the Arp2/3 complex to stimulate actin polymerization, thus changing the migratory and invasive capabilities of CRC cells. The interaction of LASP1 with N-WASP did not influence the expression of N-WASP but recovered the reduced actin polymerization induced by N-WASP silencing. High N-WASP expression was detected in most clinical colorectal samples, and it was positively correlated with the expression of LASP1 and ARP3, as well as the tumour budding and pattern of invasion, but negatively correlated with host lymphocytic response. Our study suggests a new mechanism for LASP1-mediated CRC metastasis determined by exploring LASP1-interacting proteins and identifies N-WASP as a potential therapeutic target for CRC.

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Fig. 1: N-WASP interacts with LASP1 in CRC.
Fig. 2: N-WASP stimulates the migration and invasion of CRC cells.
Fig. 3: N-WASP interacts with LASP1 to stimulate the actin polymerization.
Fig. 4: N-WASP interacts with ARP3 in CRC cells.
Fig. 5: The clinical significance of N-WASP.
Fig. 6: Sketch map illustrated the mechanism of N-WASP in LASP medicated CRC metastasis.

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Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81773082, 81702903, 81872423, 81972813), Guangdong Natural Science Foundation (2018B030311036, 2019A1515010974) and Fork Ying Tung Education Foundation (161035).

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Author notes

  1. These authors contributed equally: Pingping Yan, Jian Liu, Rui Zhou

Authors and Affiliations

  1. Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Pingping Yan, Jian Liu, Rui Zhou, Chuang Lin, Lijun Xu & Liang Zhao

  2. Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

    Pingping Yan, Jian Liu, Rui Zhou, Lijun Xu & Liang Zhao

  3. Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, China

    Pingping Yan, Jian Liu, Rui Zhou, Lijun Xu & Liang Zhao

  4. Department of Pathology, Guangdong Women and Children Hospital, 511442, Guangdong, China

    Kunhe Wu

  5. Gastrointestinal Surgical Center, The First Affiliated Hospital of Sun Yat-Sen University, 510080, Guangzhou, China

    Shibin Yang

  6. Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-Sen University, 510080, Guangzhou, China

    Shuai Yang

  7. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, China

    Jueyu Zhou

  8. Department of Medical Oncology, Affiliated Tumor Hospital of Guangzhou Medical University, Guangzhou, China

    Hui Wang

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Contributions

LZ led study design and prepared the paper; P-PY, JL and RZ carried out the experiments; CL, S-BY, and SY assisted in tissue sample collection and clinical analysis; K-HW and J-YZ performed statistical analysis; L-JX, and HW performed data analysis and interpretation.

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Correspondence to Liang Zhao.

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Yan, P., Liu, J., Zhou, R. et al. LASP1 interacts with N-WASP to activate the Arp2/3 complex and facilitate colorectal cancer metastasis by increasing tumour budding and worsening the pattern of invasion. Oncogene 39, 5743–5755 (2020). https://doi.org/10.1038/s41388-020-01397-7

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