Suppression of mutant Kirsten-RAS (KRAS G12D )-driven pancreatic carcinogenesis by dual-specificity MAP kinase phosphatases 5 and 6.

Autor: Kidger AM; Stress Response Laboratory, Jacqui Wood Cancer Centre, Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK., Saville MK; Stress Response Laboratory, Jacqui Wood Cancer Centre, Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK., Rushworth LK; Stress Response Laboratory, Jacqui Wood Cancer Centre, Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK., Davidson J; Stress Response Laboratory, Jacqui Wood Cancer Centre, Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK., Stellzig J; Stress Response Laboratory, Jacqui Wood Cancer Centre, Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK., Ono M; Stress Response Laboratory, Jacqui Wood Cancer Centre, Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK., Kuebelsbeck LA; Department of Surgery, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany., Janssen KP; Department of Surgery, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany., Holzmann B; Department of Surgery, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany., Morton JP; Institute of Cancer Sciences, Garscube Estate, Switchback Road, Glasgow, G61 1QH, UK.; CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK., Sansom OJ; Institute of Cancer Sciences, Garscube Estate, Switchback Road, Glasgow, G61 1QH, UK.; CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK., Caunt CJ; Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK., Keyse SM; Stress Response Laboratory, Jacqui Wood Cancer Centre, Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK. s.m.keyse@dundee.ac.uk.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2022 May; Vol. 41 (20), pp. 2811-2823. Date of Electronic Publication: 2022 Apr 13.
DOI: 10.1038/s41388-022-02302-0
Abstrakt: The cytoplasmic phosphatase DUSP6 and its nuclear counterpart DUSP5 are negative regulators of RAS/ERK signalling. Here we use deletion of either Dusp5 or Dusp6 to explore the roles of these phosphatases in a murine model of KRAS G12D -driven pancreatic cancer. By 56-days, loss of either DUSP5 or DUSP6 causes a significant increase in KRAS G12D -driven pancreatic hyperplasia. This is accompanied by increased pancreatic acinar to ductal metaplasia (ADM) and the development of pre-neoplastic pancreatic intraepithelial neoplasia (PanINs). In contrast, by 100-days, pancreatic hyperplasia is reversed with significant atrophy of pancreatic tissue and weight loss observed in animals lacking either DUSP5 or DUSP6. On further ageing, Dusp6 -/- mice display accelerated development of metastatic pancreatic ductal adenocarcinoma (PDAC), while in Dusp5 -/- animals, although PDAC development is increased this process is attenuated by atrophy of pancreatic acinar tissue and severe weight loss in some animals before cancer could progress. Our data suggest that despite a common target in the ERK MAP kinase, DUSP5 and DUSP6 play partially non-redundant roles in suppressing oncogenic KRAS G12D signalling, thus retarding both tumour initiation and progression. Our data suggest that loss of either DUSP5 or DUSP6, as observed in certain human tumours, including the pancreas, could promote carcinogenesis.
(© 2022. The Author(s).)
Databáze: MEDLINE
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