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Carcinogenesis Advance Access published online on January 20, 2005
Carcinogenesis, doi:10.1093/carcin/bgi027
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Oxford University Press
Received August 19, 2004
Revised December 15, 2004
Accepted January 11, 2005

CANCER BIOLOGY

Osteopontin silencing by small interfering RNA suppresses in vitro and in vivo CT26 murine colon adenocarinoma metastasis

Philip Y. Wai 1*, Zhiyong Mi 1, Hongtao Guo 1, Shiva Sarraf-Yazdi 1, Chengjiang Gao 1, Junping Wei 1, Carlos E. Marroquin 1, Bryan Clary 1, and Paul C. Kuo 1

1 Duke University Medical Center, Surgery, Durham, NC, USA

* To whom correspondence should be addressed.
Philip Y. Wai, E-mail: philip.wai{at}duke.edu


  Abstract

Hepatic metastasis is a primary cause for failure of locoregional therapy in colorectal cancer. Increased expression of osteopontin (OPN), a ligand for {alpha}v{beta}3 integrin and CD44 receptors, is associated with metastasis in several types of cancer. However, the mechanism by which OPN mediates metastasis in colorectal cancer remains unknown. We hypothesized that OPN mediates invasion of colon cancer cells through basement membrane and migration through extra-cellular matrix (ECM). In this study, we used CT26 murine colon adenocarinoma cells syngeneic to BALB/c mice to generate cell lines (pS-OPN) in which OPN expression was suppressed through small interfering RNA (siRNA) plasmids. CT26 (WT) and CT26 cells stably expressing murine-mismatch siRNA (pS-MM) served as controls. Western blotting quantified OPN protein levels and our most down-regulated clone, pS-OPN-A4, demonstrated a mean 3.0-fold decrease in OPN protein expression vs. WT. In vitro cell motility and invasiveness were decreased in pS-OPN-A4 by 3.6-fold (P = 0.004 vs. WT) and 4.1-fold (P = 0.01 vs. WT), but proliferation was similar amongst cell-lines. We demonstrated that OPN suppression significantly correlates with MMP-2 down-regulation. In vivo hepatic metastasis was assessed by quantifying liver weights and surface tumor nodules in 33 BALB/c mice (11/group) subjected to intrasplenic injection of tumor cells. pS-OPN-A4 resulted in a 50.4% decrease in mean liver weight compared to WT (3.79 ± 1.49 g vs.1.88 ± 1.34 g, P = 0.009). Only 18% of pS-OPN-A4 livers had >20 metastatic surface nodules compared to 89% for WT and 75% for pS-MM-V6. This study demonstrates that RNA interference stably reduces CT26 tumor expression of OPN and significantly attenuates CT26 colon cancer metastasis by diminishing tumor cell motility and invasiveness.

Keywords: osteopontin; cancer; liver; metastasis; siRNA; RNAi; CT26.
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