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Osteopontin Promotes Integrin Activation through Outside-In and Inside-Out Mechanisms: OPN-CD44_V Interaction Enhances Survival in Gastrointestinal Cancer Cells

¹ Institute of Biomedical Sciences, Academia Sinica; Institutes of ² Biochemistry, ³ Pharmacology, and ⁴ Genome Sciences, National Yang-Ming University; ⁵ Department of Medical Research and Education, Veterans General Hospital, Taipei, Taiwan, Republic of China

Requests for reprints: Jeou-Yuan Chen, Institute of Biomedical Sciences, Academia Sinica, 128 Section 2 Academia Road, Taipei 11529, Taiwan, Republic of China. Phone: 886-2-27899046; Fax: 886-2-27858594; E-mail: bmchen{at}ibms.sinica.edu.tw.

Osteopontin (OPN) and splice variants of CD44 (CD44_V) have independently been identified as markers for tumor progression. In this study, we show that both OPN and CD44_V are frequently overexpressed in human gastric cancer and that OPN-engaged CD44_V ligation confers cells an increased survival mediated through integrin activation. First, we show that OPN treatment confers cells an increased resistance to UV-induced apoptosis. The OPN-mediated antiapoptosis is dependent on the expression of the variant exon 6 (V6)- or V7-containing CD44 as shown by overexpression of individual CD44_V in gastric AZ521 cells that express no or very low level of endogenous CD44 and by knockdown of the constitutively expressed V6-containing CD44 isoforms in colon HT29 cells. Although OPN also interacts with RGD integrins, OPN-RGD sequence is dispensable for OPN-mediated antiapoptosis. OPN-induced antiapoptosis is mainly attributed to the engagement of CD44_V isoforms and the relay of an inside-out signaling via Src activity, leading to robust integrin activation. Furthermore, OPN-elicited antiapoptosis was observed when cells were plated on fibronectin but not on poly-D-lysin, and preincubation of cells with anti-integrin ß₁ antibody to block integrin-extracellular matrix (ECM) interaction or ectopic expression of the dominant-negative forms of focal adhesion kinase to block ECM-derived signal abolished OPN-induced survival, suggesting that OPN-elicited antiapoptotic function is propagated from matrix transduced by integrin. Taken together, we showed that OPN-CD44_V interaction promotes ECM-derived survival signal mediated through integrin activation, which may play an important role in the pathogenic development and progression of gastric cancer. [Cancer Res 2007;67(5):2089–97]

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