Cascio Sandra, Finn Olivera J
Department of Immunology, University of Pittsburgh School of Medicine, E1040 Biomedical Science Tower, Pittsburgh, PA 15261, USA.
Fondazione Ri.Med, via Bandiera, Palermo 90133, Italy.
Cancers (Basel). 2015 Feb 10;7(1):342-52. doi: 10.3390/cancers7010342.
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.
我们之前报道过，CIN85是一种85千道尔顿的蛋白质，已知其通过与Cbl相互作用参与肿瘤细胞迁移和转移，在肿瘤细胞中它与MUC1相关联。MUC1/CIN85复合物在体外也调节肿瘤细胞的迁移和侵袭。在此，我们通过免疫组织化学专门检测了人结肠癌组织芯片（TMA）中MUC1和CIN85的表达及其在癌症进展和转移中的潜在作用。我们检测到MUC1和CIN85的表达均显著增加，且与肿瘤晚期和淋巴结转移相关。我们进一步研究了Cbl是否也存在于MUC1/CIN85复合物中。免疫共沉淀分析表明，在人结肠癌细胞系中，Cbl与CIN85以及MUC1均共定位。为了开始研究MUC1过表达以及与CIN85和Cbl的关联在癌症发生和进展中的体内相关性，我们使用了在结肠上皮细胞上表达MUC1的人MUC1转基因小鼠，用氧化偶氮甲烷启动并联合葡聚糖硫酸钠（AOM/DSS）促进结直肠癌发生。与野生型小鼠相比，MUC1转基因小鼠显示出更高的肿瘤发生率和更低的存活率。与体外数据一致，在AOM/DSS处理的MUC1转基因小鼠的结肠组织中检测到了MUC1、CIN85和Cbl的关联。MUC1/CIN85/Cbl复合物似乎有助于结肠癌的促进和进展，因此早期结肠癌中MUC1、CIN85和Cbl表达的增加可能预示着预后不良。
