title: 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.
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.|Immunology Programme, Life Science Institute, National University of Singapore, Singapore, Singapore.
authors.forename: C W
authors.initials: CW
authors.lastname: Png
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.|Immunology Programme, Life Science Institute, National University of Singapore, Singapore, Singapore.
authors.forename: M
authors.initials: M
authors.lastname: Weerasooriya
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: J
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.|Immunology Programme, Life Science Institute, National University of Singapore, Singapore, Singapore.
authors.forename: S J
authors.initials: SJ
authors.lastname: James
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.|Immunology Programme, Life Science Institute, National University of Singapore, Singapore, Singapore.
authors.forename: H M
authors.initials: HM
authors.lastname: Poh
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: M
authors.initials: M
authors.lastname: Osato
authors.affiliation: Department of Immunology, Howard Hughes Medical Institute, Yale University, New Haven, CT, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing, China.
authors.forename: C
authors.initials: C
authors.lastname: Dong
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.|Immunology Programme, Life Science Institute, National University of Singapore, Singapore, Singapore.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000235:genetics; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D016264:Dextran Sulfate / Q000633:toxicity; D054637:Dual-Specificity Phosphatases / Q000235:genetics* / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006801:Humans; D007422:Intestines / Q000166:cytology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics* / Q000378:metabolism; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
chemical_list: C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors; D016264:Dextran Sulfate; D048049:Extracellular Signal-Regulated MAP Kinases; C120407:DUSP10 protein, human; C505617:Dusp10 protein, mouse; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054637:Dual-Specificity Phosphatases