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Elevated hydrostatic pressure enhances the motility and enlarges the size of the lung cancer cells through aquaporin upregulation mediated by caveolin-1 and ERK1/2 signaling

Oncogene volume 36, pages 863–874 (2017)Cite this article

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Abstract

The mechanical characteristics presented in cancer microenvironment are known to have pivotal roles in cancer metastasis, which accounts for the leading cause of death from malignant tumors. However, while a uniformly distributed high interstitial fluid pressure (IFP) is a common feature in solid tumors, the effects of high IFP on the motility and invasiveness of cancer cells remain obscure. Using cell-culture devices that simulated increased IFP conditions by applying hydrostatic pressure (HP) ranging from 0 to 20 mm Hg to the cells, we found that the elevated HPs increased the migration speeds, invasiveness, cell volume, filopodial number and aquaporin-1 (AQP1), Snail and vinculin expression levels, as well as phosphorylation of caveolin-1 and extracellular signal–regulated kinase1/2 (ERK1/2), in the lung cancer cells CL1-5 and A549. The increases of migration speed and cell volume correlated temporally with the increase of AQP1 expression. The elevated HP-induced migration acceleration was hindered by AQP1 knockdown using small interfering RNA (siRNA) transfection. Inhibition of ERK1/2 phosphorylation using the mitogen-activated protein kinase kinase inhibitor PD98059 abrogated the elevated HP-induced AQP1 upregulation and migration acceleration in the cancer cells. Caveolin-1 knockdown by siRNA transfection attenuated the HP-induced, ERK1/2-depedent AQP1 upregulation and migration acceleration. Further biochemical studies revealed that the caveolin-1 activation-driven ERK1/2 signaling is mediated by Akt1/2 phosphorylation. By contrast, the elevated HPs had negligible effects on the migration speed and volume of normal bronchial epithelial cells. These results disclose a novel mechanism relating high IFP to the invasiveness of cancer cells and highlight potential targets to impede cancer spreading.

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Acknowledgements

This work was supported by the grants from the Taiwan Ministry of Science of Technology (Grant Nos. MOST 102-2221-E-002-066, 103-2320-B-002-004-MY3 and 103-2112-M-001-019-MY3).

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Authors and Affiliations

  1. Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan

    Y-C Kao, J-R Jheng & P-L Kuo

  2. Research Center for Applied Sciences, Academia Sinica, Taipei, Taiwan

    Y-C Kao, H-J Pan & C-H Lee

  3. Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

    W-Y Liao

  4. Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan

    C-H Lee

  5. Department of Physics, National Taiwan University, Taipei, Taiwan

    C-H Lee

  6. Department of Electrical Engineering, National Taiwan University, Taipei, Taiwan

    P-L Kuo

  7. Department of Rehabilitation, National Taiwan University Hospital, Taipei, Taiwan

    P-L Kuo

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Kao, YC., Jheng, JR., Pan, HJ. et al. Elevated hydrostatic pressure enhances the motility and enlarges the size of the lung cancer cells through aquaporin upregulation mediated by caveolin-1 and ERK1/2 signaling. Oncogene 36, 863–874 (2017). https://doi.org/10.1038/onc.2016.255

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