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Netrin-1 elicits metastatic potential of non-small cell lung carcinoma cell by enhancing cell invasion, migration and vasculogenic mimicry via EMT induction

Cancer Gene Therapy volume 25, pages 18–26 (2018)Cite this article

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Abstract

Ectopic expression of netrin-1 has been validated in several cancers including non-small cell lung cancer (NSCLC). Recent research confirms the critical role of netrin-1 in NSCLC growth and its prognostic value. Unfortunately, its contribution in NSCLC metastasis remains elusive. Here, netrin-1 had relatively high expression in NSCLC tissues and cells, especially in high metastatic groups. Notably, netrin-1 overexpression aggravated the malignant metastatic behavior of NSCLC cells, including cell invasion, migration, and vasculogenic mimicry (VM), whereas netrin-1 depression reversely dampened the metastatic potential. Mechanism analysis confirmed that elevation of netrin-1 induced the typical morphological changes of epithelial-to-mesenchymal transition (EMT) and increased the expression of EMT markers, including E-cadherin down-regulation and N-cadherin up-regulation. Consistently, netrin-1 inhibition inversely antagonized the occurrence of EMT. Moreover, netrin-1 also activated the oncogenic pathways of PI3K/AKT and ERK signaling. More importantly, blocking these pathways with their antagonists LY294002 or U0126 reversed the effects of netrin-1 overexpression on cell invasion, migration, EMT, and VM formation. Collectively, the current data suggest that netrin-1 can act as a pro-metastatic factor in NSCLC by enhancing cell invasion, migration, and VM via PI3K/AKT and ERK-mediated EMT process, thereby implicating netrin-1 as a novel promising therapeutic target against aggressive NSCLC.

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Acknowledgements

Financial support was provided by Research Fund of the First Affiliated Hospital of Harbin Medical University (No. 2017Y013).

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Authors and Affiliations

  1. Department of Respiration, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, P. R. China

    Xiaofei Zhang, Kaiyu Han, Jianing Li & Hong Chen

  2. Department of Gynaecology, Harbin Medical University Cancer Hospital, Harbin, 150081, P. R. China

    Ping Cui

  3. Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, P. R. China

    Beichen Ding

  4. Department of Respiration, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, P. R. China

    Yuening Guo & Wei Zhang

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  1. Xiaofei Zhang
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Correspondence to Wei Zhang.

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Zhang, X., Cui, P., Ding, B. et al. Netrin-1 elicits metastatic potential of non-small cell lung carcinoma cell by enhancing cell invasion, migration and vasculogenic mimicry via EMT induction. Cancer Gene Ther 25, 18–26 (2018). https://doi.org/10.1038/s41417-017-0008-8

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