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LPP inhibits collective cell migration during lung cancer dissemination

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Abstract

Lipoma preferred partner (LPP) is a LIM domain protein, which has multiple functions as an actin-binding protein and a transcriptional coactivator, and it has been suggested that LPP has some roles in cell migration or invasion, however, its role in cancer cells remains to be elucidated. Here, we showed that LPP degraded N-cadherin in lung cancer, PC14PE6 cells via regulating the expression of matrix metalloproteinase 15 (MMP-15), and loss-of-LPP increases collective cell migration (CCM) and dissemination consequently. Knockdown of LPP and its functional partner, Etv5, markedly restores the full-length N-cadherin and increases cell–cell adhesion. We investigated the common target of LPP and Etv5, and found that MMP-15 is transcribed as their direct transcriptional target. Furthermore, MMP-15 could directly digest the N-cadherin extracellular domain. LPP knockdown in PC14PE6 cells increases N-cadherin-dependent CCM in the three-dimensional collagen gel invasion assays, and promoted the dissemination of cancer cells when they were orthotopically implanted in nude mice. Immunohistochemistry of lung adenocarcinoma specimens revealed the heterogeneity of LPP intensity and complementary expression of LPP and N-cadherin in the primary tumors. These findings suggest that loss-of-LPP, Etv5 or MMP-15 can be a prognostic marker of increasing malignancy.

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Acknowledgements

We thank Dr Yuichiro Hamanaka for kindly providing the melanoma cell lines. The MNCD2 antibody developed by Takeichi and Matsunami was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of NICHD and maintained by Department of Biology, The University of Iowa, Iowa City, IA, USA. This work is supported by JST KAKENHI (grant number 24700962, SK; grant number 25290042, 26640068, MT) and MEXT KAKENHI (grant number 25111702, SK).

Author Contributions

SK performed the experiments. SY and TK provided the set of lung cancer cell lines. MY, YM and AG made human cancer patient specimens. NA, MT and AG analyzed IHC of patient specimens. SK and MT designed the experiments, and wrote the manuscript.

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Authors and Affiliations

  1. Department of Molecular Medicine and Biochemistry, Graduate School and Faculty of Medicine, Akita University, Akita, Japan,

    S Kuriyama, N Aiba & M Tanaka

  2. Department of Cellular and Organ pathology, Graduate School of and Faculty of Medicine, Akita University, Akita, Japan,

    M Yoshida & A Goto

  3. Division of Medical Oncology, Cancer Therapeutics Development Program, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

    S Yano

  4. Division of Genome Biology, Group for Development of Molecular Diagnostics and Individualized Therapy, National Cancer Research Center Institute, Chiba, Japan

    T Kohno

  5. Department of Thorasic Surgery, Akita University, Akita, Japan,

    Y Minamiya

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  1. S Kuriyama
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  2. M Yoshida
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  3. S Yano
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  4. N Aiba
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Correspondence to M Tanaka.

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Kuriyama, S., Yoshida, M., Yano, S. et al. LPP inhibits collective cell migration during lung cancer dissemination. Oncogene 35, 952–964 (2016). https://doi.org/10.1038/onc.2015.155

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