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Netrin-1 promotes the collective cell migration of liver cancer cells in a 3D cell culture model

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Abstract

Collective cell migration plays an important role in embryonic development, wound healing, and cancer metastasis. We aimed to investigate the expression, role, and mechanism of Netrin-1 in collective cell migration using a3D culture model. An immunohistochemical study showed that certain cells invaded surrounding tissue by collective migration and that Netrin-1 expression in these cells was increased, especially at the invasive front. In the 3D culture model, collective cell migration was clearly observed, as leader cells were followed by cells migrating along a canal. N-cadherin-mediated cell junctions were observed in collective cell migration, and Netrin-1 expression was elevated in these cells. Netrin-1 did not affect the expression of N-cadherin in 2D-cultured cells; however, in 3D culture, the overexpression of Netrin-1 increased N-cadherin and promoted the collective migration of Huh7 cells, while the knockdown of Netrin-1 decreased N-cadherin and inhibited collective migration in SK-Hep-1 cells. Interestingly, N-cadherin knockdown in Huh7 cells significantly diminished Netrin-1-promoted collective cell migration, while the overexpression of N-cadherin restored collective migration in Netrin-1-knockdown SK-Hep1 cells. These results suggest that Netrin-1 enhances N-cadherin junctions to promote liver cancer cell collective migration in 3D cell culture and may subsequently increase liver cancer metastasis.

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Funding

This study was supported by the National Natural Science Foundation of China (No. 81472311, No. 81572419, and No. 81702396).

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Authors and Affiliations

  1. Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Avenue, Wuhan, 430030, People’s Republic of China

    Ping Han, Jingmei Liu, Yu Lei, Zhuoying Lin, Dean Tian & Wei Yan

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  1. Ping Han
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  2. Jingmei Liu
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  3. Yu Lei
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  4. Zhuoying Lin
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  5. Dean Tian
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Correspondence to Dean Tian or Wei Yan.

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This study was performed according to the guidelines of the Ethics Committee of the Tongji Hospital and approved in accordance with the ethical standards of the World Medical Association Declaration of Helsinki.

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Han, P., Liu, J., Lei, Y. et al. Netrin-1 promotes the collective cell migration of liver cancer cells in a 3D cell culture model. J Physiol Biochem 75, 489–498 (2019). https://doi.org/10.1007/s13105-019-00701-8

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