Expression of the MAP kinase phosphatase DUSP4 is associated with microsatellite instability in colorectal cancer (CRC) and causes increased cell proliferation

DUSP4 (MKP‐2), a member of the mitogen‐activated protein kinase phosphatase (MKP) family and potential tumor suppressor, negatively regulates the MAPKs (mitogen‐activated protein kinases) ERK, p38 and JNK. MAPKs play a crucial role in cancer development and progression. Previously, using microarray analyses we found a conspicuously frequent overexpression of DUSP4 in colorectal cancer (CRC) with high frequent microsatellite instability (MSI‐H) compared to microsatellite stable (MSS) CRC. Here we studied 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. DUSP4 was overexpressed in all 19 MSI‐H tumors and in 14 MSS tumors. Median expression levels in MSI‐H tumors were significantly higher than in MSS‐tumors (p < 0.001). Consistently, MSI‐H CRC cell lines showed 6.8‐fold higher DUSP4 mRNA levels than MSS cell lines. DUSP4 expression was not regulated by promoter methylation since no methylation was found by quantitative methylation analysis of DUSP4 promoter in CRC cell lines neither in tumor samples. Furthermore, no DUSP4 mutation was found on genomic DNA level in four CRC cell lines. DUSP4 overexpression in CRC cell lines through DUSP4 transfection caused upregulated expression of MAPK targets CDC25A, CCND1, EGR1, FOS, MYC and CDKN1A in HCT116 as well as downregulation of mismatch repair gene MSH2 in SW480. Furthermore, DUSP4 overexpression led to increased proliferation in CRC cell lines. Our findings suggest that DUSP4 acts as an important regulator of cell growth within the MAPK pathway and causes enhanced cell growth in MSI‐H CRC. What's new? Mitogen‐activated protein kinase phosphatases (MKPs) play a crucial role in regulating cell signaling pathways associated with cancer development and progression. In colorectal cancer, the correlation of expression of the MKP family member DUSP4 with microsatellite instability, reported for the first time here, suggests that these phosphatases, and DUSP4 specifically, could be potential biomarkers. These findings were further supported by in vitro analyses of DUSP4 overexpression, which altered the expression of genes involved in DNA repair and cell proliferation.