Institute of Pathology and Molecular Pathology Diagnostic Unit, University of Regensburg, Germany.
Int J Cancer. 2013 Apr 1;132(7):1537-46. doi: 10.1002/ijc.27834. Epub 2012 Nov 23.
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.
DUSP4（MKP-2）是丝裂原活化蛋白激酶磷酸酶（MKP）家族的成员，也是一种潜在的肿瘤抑制因子，它负向调节丝裂原活化蛋白激酶（MAPKs）ERK、p38 和 JNK。MAPKs 在癌症的发生和发展中起着至关重要的作用。之前，我们通过微阵列分析发现，与微卫星稳定（MSS）CRC 相比，具有高频繁微卫星不稳定性（MSI-H）的结直肠癌（CRC）中 DUSP4 的表达显著频繁上调。在这里，我们通过 RT-qPCR 研究了 38 例 CRC（19 例 MSI-H 和 19 例 MSS）中 DUSP4 的 mRNA 水平表达，以及与匹配的正常组织和 CRC 细胞系中的表达。19 例 MSI-H 肿瘤和 14 例 MSS 肿瘤中均过度表达 DUSP4。MSI-H 肿瘤中的中位表达水平明显高于 MSS 肿瘤（p<0.001）。一致地，MSI-H CRC 细胞系的 DUSP4 mRNA 水平比 MSS 细胞系高 6.8 倍。DUSP4 的表达不受启动子甲基化的调节，因为在 CRC 细胞系和肿瘤样本中，通过定量甲基化分析未发现 DUSP4 启动子的甲基化。此外，在四个 CRC 细胞系的基因组 DNA 水平上未发现 DUSP4 突变。通过 DUSP4 转染在 CRC 细胞系中过度表达 DUSP4 导致 HCT116 中 MAPK 靶标 CDC25A、CCND1、EGR1、FOS、MYC 和 CDKN1A 的表达上调，以及 SW480 中错配修复基因 MSH2 的下调。此外，DUSP4 的过度表达导致 CRC 细胞系的增殖增加。我们的研究结果表明，DUSP4 作为 MAPK 途径中细胞生长的重要调节剂，导致 MSI-H CRC 中细胞生长增强。
