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DUSP10 regulates intestinal epithelial cell growth and colorectal tumorigenesis

Abstract

Dual specificity phosphatase 10 (DUSP10), also known as MAP kinase phosphatase 5 (MKP5), negatively regulates the activation of MAP kinases. Genetic polymorphisms and aberrant expression of this gene are associated with colorectal cancer (CRC) in humans. However, the role of DUSP10 in intestinal epithelial tumorigenesis is not clear. Here, we showed that DUSP10 knockout (KO) mice had increased intestinal epithelial cell (IEC) proliferation and migration and developed less severe colitis than wild-type (WT) mice in response to dextran sodium sulphate (DSS) treatment, which is associated with increased ERK1/2 activation and Krüppel-like factor 5 (KLF5) expression in IEC. In line with increased IEC proliferation, DUSP10 KO mice developed more colon tumours with increased severity compared with WT mice in response to administration of DSS and azoxymethane (AOM). Furthermore, survival analysis of CRC patients demonstrated that high DUSP10 expression in tumours was associated with significant improvement in survival probability. Overexpression of DUSP10 in Caco-2 and RCM-1 cells inhibited cell proliferation. Our study showed that DUSP10 negatively regulates IEC growth and acts as a suppressor for CRC. Therefore, it could be targeted for the development of therapies for colitis and CRC.

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Acknowledgements

We would like to thank Nicholas Gascoigne for advice and helpful discussion. This study was supported by grants from the Office of Deputy President, National University of Singapore, the Ministry of Education (MOE2010-T2-1-079) and the National Medical Research Council (IRG10nov091 and CBRG11nov101) of Singapore.

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Png, C., Weerasooriya, M., Guo, J. et al. DUSP10 regulates intestinal epithelial cell growth and colorectal tumorigenesis. Oncogene 35, 206–217 (2016). https://doi.org/10.1038/onc.2015.74

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