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An osteopontin fragment is essential for tumor cell invasion in hepatocellular carcinoma

Oncogene volume 26, pages 6361–6371 (2007)Cite this article

Abstract

Tumor cell invasion is a primary event in the metastatic progression of hepatocellular carcinoma (HCC). Our recent results indicate a concordant elevated expression of osteopontin (OPN) and matrix metalloproteinase-9 (MMP-9) in primary metastatic HCC. This study hypothesizes an MMP-9-directed cleavage of OPN that biologically contributes to HCC metastasis. We found that MMP-9 cleaved OPN into specific fragments in vitro, of which three could be identified by Edman degradation amino-acid sequencing. One of these fragments (OPN-5 kDa, residues 167–210) induced low-metastatic HCC cellular invasion via CD44 receptors, which was effectively blocked by the addition of small peptides within the region of OPN-5 kDa. Increased expression of an OPN splice variant (OPN-c) was associated with clinical metastatic HCC. Overexpression of OPN-c with physiological levels of MMP-9 enhanced cellular invasion and coincided with elevated OPN-5 kDa levels. Our data suggest that an alternative splicing event (OPN-c) promotes extracellular cleavage of OPN by MMP-9, thus releasing a distinct region of OPN (OPN-5 kDa) that is essential for HCC cellular invasion and appears to correlate with metastatic potential. The findings of this study may help to improve advanced-stage HCC prognosis and suggest the utility of small peptides for novel therapies.

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Abbreviations

HCC:

hepatocellular carcinoma

MMP-9:

matrix metalloproteinase-9

OPN:

osteopontin

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Acknowledgements

This work was supported by intramural funding at the Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. The authors thank Dominic Esposito of the SAIC-Frederick Protein Expression Lab, Frederick, MD, USA for help with cloning of the OPN expression constructs. We also thank Curtis Harris and Anuradha Budhu for critical comments and the NIH Fellows Editorial Board for editorial review of this manuscript.

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Authors and Affiliations

  1. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    V Takafuji, M Forgues & X W Wang

  2. Antibody and Protein Purification Group, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    E Unsworth & P Goldsmith

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  1. V Takafuji
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  2. M Forgues
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Correspondence to X W Wang.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Takafuji, V., Forgues, M., Unsworth, E. et al. An osteopontin fragment is essential for tumor cell invasion in hepatocellular carcinoma. Oncogene 26, 6361–6371 (2007). https://doi.org/10.1038/sj.onc.1210463

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