Article Abstract

The clinical and biological implications of N-WASP expression in human colorectal cancer

Authors: Tracey A. Martin, Ann-Marie Toms, Leigh Mansel Davies, Shan Cheng, Wen G. Jiang

Abstract

Backgrounds: Neural Wiskott-Aldrich Syndrome protein, N-WASP, a member of the WASP family proteins is a regulator of ARP2/3 and cytoskeleton in the cells and has been implicated in regulating cell motility and morphology. N-WASP has been implicated in the development and progression of certain solid tumours. In the present study, we initially investigated the expression levels of N-WASP in a cohort of human colorectal cancers and explored the relationship between N-WASP and clinical outcome. We further examined the impact of N-WASP on the biological functions of colon cancer cells.
Material and methods: A cohort of fresh frozen human colon tissues were used. N-WASP protein in tissues was analysed using an immunohistochemical method. N-WASP transcripts in the tissues were quantified using real-time quantitative PCR methods and correlated with clinical and pathological information of the patients together with clinical outcome. Human colon cancer cell line, HRT18, weakly positive for N-WASP was genetically modified to either over-express N-WASP or to lose N-WASP expression by way of ribozyme transgenes. Cell functions were determined after the genetic manipulation.
Results: Colonic epithelial cells stained positive for N-WASP with the staining mainly in the cytoplasmic region of the cells. However, colon tumour cells had greatly reduced N-WASP staining. The reduction of N-WASP protein was well reflected at message level, in that colon tumour tissues had significantly lower levels of N-WASP transcript compared with normal tissues (p<0.001). Significantly lower levels of N-WASP transcript were seen in node positive tumours and tumour with muscular invasion. Patients with low levels of N-WASP transcript had short overall and disease free survivals. Over-expression of N-WASP markedly reduced the adhesion, cellular motility and invasiveness of HRT18 cells. Likewise, knocking down N-WASP resulted in an increase in matrix adhesion and invasion, which was blocked by FAK (focal adhesion kinase) inhibitor.
Conclusions: N-WASP expression is aberrant in human colon cancer. A reduction of N-WASP in colon tumours is associated with disease progression and a poor clinical outcome of the patients. In addition, N-WASP expression in colon cancer cells is inversely correlated with the aggressiveness of the cells, namely adhesion and invasiveness. Collectively, this study indicates that N-WASP carries the hallmark of a tumour metastasis suppressor in human colon cancer. This is likely to be via a FAK mediated pathway.

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