Abstract 4108: Syndecan-1 overexpression enhances colon cancer growth by modulating heparan sulfate binding growth factors sensitivity

Abstract

Abstract Syndecan-1 is a multifaceted transmembrane heparan sulfate proteoglycan known for its significant role in a wide range of cellular processes by interacting with a multitude of extracellular components. Although loss of syndecan-1 correlates well with the gain of cancerous characteristics in a wide range of cancers, increased expression of syndecan-1 also corresponds to adverse outcomes in some cancers. The biological function is yet to be completely understood in most of malignancies, including colon cancer. In the present study, to evaluate biological functions of syndecan-1, its expression level was altered, and subsequent outcomes were examined using human colon cancer LoVo cells. Ectopic expression of syndecan-1 in LoVo cells (LoVo/SDC1) led to larger tumor formation than did control LoVo cells (LoVo/mock) in mice. Lower concentrations of HB-EGF and HGF could activate their receptors in LoVo/SDC1 than in LoVo/mock. And, the prolonged phosphorylation of EGFR induced by HB-EGF was observed in LoVo/SDC1. Furthermore, HB-EGF more effectively promoted cell growth of LoVo/SDC1 than that of LoVo/mock. Blockade of syndecan-1 using small-interfering RNA (siRNA) gene knockdown canceled sensitization of LoVo/SDC1 to HB-EGF and diminished LoVo/SDC1 cell growth stimulated by HB-EGF. These results suggest that syndecan-1 overexpression may contribute to heparan sulfate binding growth factors sensitization and their promoting effects to cancer growth. Finally, we examined the effects of syndecan-1 on chemotherapy in the presence of heparan sulfate binding growth factors. In comparison to LoVo/mock, LoVo/SDC1 was resistant to some cytotoxic drugs (paclitaxel, 5-FU, or CPT-11) in the presence of HB-EGF or HGF. Blockade of syndecan-1 using siRNA diminished chemotherapy resistance of LoVo/SDC1 caused by HB-EGF. These findings demonstrate that syndecan-1 confers chemotherapy resistance in colon cancer through concomitant heparan sulfate binding growth factors sensitization. In summary, our results identify syndecan-1 as a functional coreceptor for heparan sulfate binding growth factors that activate their receptors and promote their downstream pathway in colon cancer cells. Syndecan-1 overexpression may contribute to tumor growth and the chemotherapy resistance characteristic of colon cancer. Therefore, therapeutic invention aimed at inhibiting this molecule may be useful in cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4108.