Abstract 5325: Role of MUC13 in colon cancer progression

Abstract

Abstract Colon cancer is the third most commonly diagnosed and second leading cause of cancer related deaths in the United States. Mucin 13 (MUC13), a high molecular weight glycoprotein, is a recently identified transmembrane mucin. While MUC13 is known to be over expressed in gastric and ovarian cancers, limited information about MUC13 is available in colon cancer progression. Therefore, our aim is to investigate the expression profile, potential role and possible regulatory pathways of MUC13 in colon cancer progression. We performed immunohistochemical analysis using MUC13 monoclonal antibody (ppz0020) to determine expression profile and aberrant localization of MUC13 in colon cancer cells. Our results indicate that MUC13 is over expressed in colon cancer predominantly at the apical surface. MUC13 is also aberrantly localized (cytoplasmic and nuclear) in metastasized colon cancer and in liver metastasis. We also correlated MUC13 expression levels with clinico-pathological parameters of patients. Increased MUC13 expression correlated with increased tumor size and poorly differentiated colon cancer. To determine the functional roles of MUC13 we generated stable MUC13 over expressing and MUC13 knock down cells and performed functional assays. Our results demonstrate that MUC13 increased cell proliferation, colony formation, cell migration and cell invasion characteristics of colon cancer cells. In order to investigate proteins that are affected by MUC13, we performed immunoblot assays. Immunoblot analysis revealed that MUC13 increased expression of several proteins that are associated with colon cancer progression and metastasis such as Bmi-1(B cell specific lymphoma moloney murine leukemia integration site-1), TERT (telomerase reverse transcriptase), Shh (sonic hedgehog) and GATA1 (GATA binding protein 1). We also examined potential signaling pathways that may be associated with MUC13 colon carcinogenesis. We found that MUC13 increased expression of mitogen activated kinase (MAPK) pathway members such as ERK-1 and phospho ERK-1. In order to determine potential transcriptions factors that may regulate MUC13 expression, we screened expression of various transcription factors by real time PCR. Significantly high expression of STAT5B (signal transducers and activators of transcription factor 5B) was detected in cell lines expressing endogenously high levels of MUC13. In order to confirm transcription factor STAT5B binding sites in the MUC13 promotor, we performed chromatin immunoprecipitation (CHIP). CHIP analysis revealed that STAT5B binds to the promoter of MUC13. In summary, our study revealed that MUC13 is over expressed in colon cancer and aberrantly localized in metastasis. Over expression of MUC13 increases cell proliferation, colony formation, cell migration, cell invasion and expression of metastasis associated proteins partly via MAPK pathway. MUC13 expression may be regulated through binding of STAT5B to the MUC13 promoter. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5325. doi:1538-7445.AM2012-5325