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Carcinogenesis Advance Access published online on August 29, 2003
Carcinogenesis, doi:10.1093/carcin/bgg139
© 2003 by Oxford University Press
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© 2003 Oxford University Press

CANCER BIOLOGY

Osteopontin-dependent CD44v6 expression and cell adhesion in HepG2 cells

Chengjiang Gao 1, Hongtao Guo 1, Laura Downey 1, Carlos Marroquin 1, Junping Wei 1, and Paul C. Kuo 1*

1 Dept. of Surgery, Duke University Medical Center, Durham, NC 27710

* Corresponding author. E-mail: kuo00004{at}mc.duke.edu.

Received 16 May 2003 ; revised 21 July 2003 ; accepted 29 July 2003

Abstract

Background: Interaction of osteopontin (OPN) with CD44 and {alpha}v{beta}3-integrin has been implicated in numerous signal transduction pathways that may promote cancer metastasis. CD44v6 is a splice variant of CD44 which has been identified as a marker of cancer progression.

Results: In this study, immortalized liver carcinoma cells (HepG2) were used to examine the effect of OPN on two isoforms of CD44: CD44 standard (CD44s) and CD44v6. Western blots demonstrated that OPN upregulated plasma membrane CD44v6 protein expression in a concentration- and time-dependent fashion. CD44v6 levels returned to control levels when OPN-{alpha}v{beta}3-integrin binding was blocked by an RGD peptide or tyrosine kinase activity was inhibited. OPN significantly increased CD44v6 protein synthesis, while simultaneously decreasing protein degradation. Steady state mRNA levels of both CD44s and CD44v6 were unaltered in the presence of OPN stimulation. OPN increased HepG2 in vitro adhesion to hyaluronate (HA); excess soluble HA extinguished OPN-mediated HepG2 adhesion indicating CD44 dependence.

Conclusion: In conclusion, OPN binds to the {alpha}v{beta}3-integrin to increase plasma membrane CD44v6 expression and augment in vitro adhesion to HA. This may contribute to the mechanism by which OPN enhances metastatic behavior in hepatocellular cancer cells.

osteopontin, CD44, metastasis, liver, cancer, {alpha}V{beta}3 integrin
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