Abstract 3075: MUC4 mucin as a potential tumor suppressor in colon cancer

Abstract

Abstract MUC4 is a heterodimeric large transmembrane mucin expressed by several normal epithelial tissues like testis, lungs and colon and is aberrantly over expressed by most human adenocarcinomas. MUC4 has been strongly implicated to play the role of an oncogene in the progression and metastasis of pancreatic, breast and ovarian cancers. On the other hand, previous reports indicating the loss of MUC4 expression in the progression of colon cancer was starkly in contrast to the role it plays in other cancers. Based on the previous studies, we hypothesized that loss of MUC4 as the tumor progresses might act as a prognostic indicator and MUC4 might act as a potential tumor suppressor in the colon cancer. In the present study, our aim was to investigate the functional significance of MUC4 in colon cancer progression. We performed immunohistochemistry on a tissue microarray comparing the expression levels of MUC4 among normal colon, adenoma, adenocarcinoma and metastatic adenocarcinoma. MUC4 immunoreactivity was highest in the normal colon tissue and significantly higher than tubular adenoma, non-metastatic and metastatic adenocarcinoma (p<0.03) which confirmed the earlier findings. To evaluate the functional significance of MUC4, we stably over expressed MUC4 cDNA in HCT-15, a MUC4 non-expressing colon cancer cell line. Interestingly, the in vitro (growth kinetics, motility, invasion, colony forming) and in vivo (xenograft in nude mice) functional studies strongly support the role of MUC4 as a tumor suppressor in colon cancer. Further, mechanistic studies indicated that ectopic expression of MUC4 led to decreased activity of key intracellular signaling molecules like FAK, AKT and ERK. By regulating the levels of p-AKT, MUC4 expression led to growth arrest in S-phase which was mediated by the upregulation of cip/kip family of CDK inhibitors i.e. p21 and p27. Besides, overexpression of MUC4 led to a remarkable change from mesenchymal like (more triangular) phenotype to a more epithelioid (roundish) like phenotype confirmed by the phalloidin staining of the actin cytoskeleton. In conclusion, our results show for the first time the protective role MUC4 plays in colon cancer. 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 3075.