Abstract
We previously reported that CIN85, an 85 KDa protein known to be involved in tumor cell migration and metastasis through its interaction with Cbl, associates with MUC1 in tumor cells. MUC1/CIN85 complex also regulates migration and invasion of tumor cells in vitro. Here, we examined specifically human colon carcinoma tissue microarrays (TMA) by immunohistochemistry for the expression of MUC1 and CIN85 and their potential role in cancer progression and metastasis. We detected a significant increase in expression of both MUC1 and CIN85 associated with advanced tumor stage and lymph node metastasis. We further investigated if Cbl could also be present in the MUC1/CIN85 complex. Co-immunoprecipitation assay showed that Cbl co-localized both with CIN85 and with MUC1 in a human colon cancer cell line. To begin to investigate the in vivo relevance of MUC1 overexpression and association with CIN85 and Cbl in cancer development and progression, we used human MUC1 transgenic mice that express MUC1 on the colonic epithelial cells, treated with azoxymethane to initiate and dextran sulfate sodium (AOM/DSS) to promote colorectal carcinogenesis. MUC1.Tg mice showed higher tumor incidence and decreased survival when compared with wild-type mice. Consistent with the in vitro data, the association of MUC1, CIN85 and Cbl was detected in colon tissues of AOM/DSS-treated MUC1 transgenic mice. MUC1/CIN85/Cbl complex appears to contribute to promotion and progression of colon cancer and thus increased expression of MUC1, CIN85 and Cbl in early stage colon cancer might be predictive of poor prognosis.
Highlights
Mucin 1 (MUC1) is a transmembrane glycoprotein expressed primarily on apical surfaces of ductal epithelia
We have previously shown that the tumor form of MUC1 and CIN85 are expressed at significantly higher levels in early and advanced stage of human breast cancer compared with normal epithelium [3]
Overexpression of MUC1 has been observed in many types of adenocarcinoma and correlated with lymph node metastasis and poor prognosis in patients [18,19,20,21]
Summary
Mucin 1 (MUC1) is a transmembrane glycoprotein expressed primarily on apical surfaces of ductal epithelia. Through the SH3 domains and the proline-rich region, CIN85 is implicated in many protein-protein interactions and it is found to play important roles in other processes such as apoptosis, rearrangement of actin cytoskeleton, cell adhesion, immunological synapse, cell migration and invasion [10,11]. It appears that CIN85 must associate with Cbl in order to regulate intracellular signaling such as the antigen receptor signaling in human B cells [12], interaction and modulation of TRAIL-induced MEKK4/p38/Akt survival network [13], and mono-ubiquitination of AMAP1 to drive invasion of breast cancer cells [14]. Our data suggest that an increase in the expression of these molecules and their co-association might play a critical role in the promotion and progression of colon and most likely other cancers
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