Abstract 2883: The expression and potential role of MUC7 in pancreatic adenocarcinoma.

Human mucin 7 (MUC7) is the smallest of the mucin core proteins at 39 kD with fully glycosylated forms ranging from 125-250 kD. This secreted, non-gel forming mucin is normally expressed by the mucousal and serosal salivary glands and sub-mucosal glands in the lower respiratory tract. MUC7 is expressed in allergic-asthma, COPD, cystic fibrosis and bladder cancer. The tandem repeat domain consists of 5-6 repeats of a 23 amino acid sequence and MUC7 has a unique histatin-like domain that binds microbes promoting clearance. We conducted immunohistochemical studies of MUC7 expression in pancreatic adenocarcinoma and found that MUC7 was expressed in over 50% of primary tumors, liver metastases, and lymph node metastases. In lymph node metastases, MUC7 was found to be primarily expressed by immune cells rather than tumor cells. In contrast, MUC7 was not expressed by infiltrating immune cells in primary tumors and liver metastases, but instead by tumor cells. MUC7 was expressed in splenocytes but not peripheral-blood mononuclear cells, suggesting its expression is in part due to inflammation or immune cell activation. Characterization of the immune cells expressing MUC7 in the lymph nodes revealed that the major types of immune cells expressing MUC7 were CD68 positive macrophages and CD11c dendritic cells. Expression of MUC7 is upregulated by IL-1β, IL-4, IL-13, TNF-α, LPS, and EGF in inflammed airways, and its minimal proximal promoter contains binding sites for NF-κB, AP1 and STAT transcription factors; all of which are involved in promoting inflammation. We found that MUC7 expression was up-regulated in the pancreatic cancer cell line Hs766T and the breast cancer cell line BT474 upon incubation with Th1 cytokines IFN-γ, IL-1β and TNF-α and the Th2 cytokines IL-4, IL-10 and IL-13. MUC7 over-expression was achieved immediately and was sustained when the cells were treated with the Th1 cytokines showing a slight time-dependent induced MUC7 expression pattern. Global gene expression by microarray was evaluated on samples of primary and metastatic pancreatic adenocarcinoma that expressed or did not express MUC7 to identify candidate genes affected by or associated with MUC7 expression. The microarray data revealed that a number of genes involved in tissue remodeling and inflammation were differentially expressed by MUC7 positive tumors. Of particular note, systems analysis showed the galectin-3 pathway to be upregulated with MUC7 expression. We detected MUC7 and galectin-3 complexes both in pancreatic cancer cell lines and in pancreatic cancer tissue samples. Together, the data from the analyses presented here led us to propose that MUC7 interacts with galectin-3 to establishing a pro-tumorigenic microenvironment possibly through enhancing components of the inflammatory response and aiding in tissue remodeling. Citation Format: Neeley A. Remmers, Paul M. Grandgenett, Fang Yu, Michael A. Hollingsworth. The expression and potential role of MUC7 in pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2883. doi:10.1158/1538-7445.AM2013-2883