Expression of the MAP kinase phosphatase DUSP4 is associated with microsatellite instability in colorectal cancer (CRC) and causes increased cell proliferation
| Autor: | Ferdinand Hofstädter, Marcus Bettstetter, Tina Bocker Edmonston, Matthias Woenckhaus, Christian Giedl, Benedikt Gröschl, Wolfgang Dietmaier |
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| Rok vydání: | 2012 |
| Předmět: |
MAPK/ERK pathway
Proto-Oncogene Proteins B-raf Cancer Research CDC25A Colon Blotting Western Apoptosis Real-Time Polymerase Chain Reaction Immunoenzyme Techniques Proto-Oncogene Proteins p21(ras) Proto-Oncogene Proteins medicine Tumor Cells Cultured Humans RNA Messenger neoplasms Cell Proliferation biology Cell growth Reverse Transcriptase Polymerase Chain Reaction Rectum Microsatellite instability Cancer DNA Methylation medicine.disease digestive system diseases Oncology MSH2 Mitogen-activated protein kinase DNA methylation Immunology Mutation biology.protein Cancer research ras Proteins Dual-Specificity Phosphatases Mitogen-Activated Protein Kinase Phosphatases Microsatellite Instability Colorectal Neoplasms |
| Zdroj: | International journal of cancer. 132(7) |
| ISSN: | 1097-0215 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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