Abstract 235: Expression of DUSP4/MKP2 increases cell growth in colorectal cancer (CRC) cells and is associated with MSI-H phenotype in CRC

Abstract

DUSP4, also termed MKP2 is a member of the mitogen-activated protein kinase phosphatase (MKP) family which negatively regulates the MAPKs (Mitogen-activated protein kinases) ERK, p38 and JNK. Using microarray analyses we found previously DUSP4 frequently overexpressed in high frequent microsatellite unstable (MSI-H) colorectal cancer CRC. Here we analysed DUSP4 expression on mRNA level in 38 CRC (19 MSI-H and 19 MSS) compared to matched normal tissue as well as in CRC cell lines by RT-qPCR. All 19 MSI-H tumors (100%) and 14/19 (73.7%) MSS tumors showed overexpressed DUSP4. However, median expression levels in MSI-H tumors were significantly higher than in MSS-tumors (p<0.001). Likewise, MSI-H CRC cell lines showed 5.1-fold higher DUSP4 mRNA levels than MSS cell lines. Using quantitative methylation analysis (MethyQESD) we did not find DUSP4 expression regulated by promoter methylation in CRC cell lines as well as in tumor samples. DUSP4 overexpression in CRC cell lines through DUSP4 transfection caused increased expression of the MAPK targets CDC25A, CCND1, EGR1, MYC and CDKN1A in HCT116 cells as well as downregulation of the mismatch repair gene MSH2 in SW480 cells. Furthermore, DUSP4 overexpression caused increased proliferation in CRC cells using Real Time Cell Analysis (RTCA) system. Our findings suggest that DUSP4 plays as an important role in regulating cell growth within the MAPK pathway and causes enhanced cell growth in MSI-H colorectal cancer. 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 235. doi:1538-7445.AM2012-235