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Cancer Sci. 2018 Jul;109(7):2178-2187. doi: 10.1111/cas.13638. Epub 2018 Jun 25.

Loss of protein phosphatase 6 in mouse keratinocytes enhances K-rasG12D -driven tumor promotion.

Author information

1
Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan.
2
Department of Plastic and Reconstructive Surgery, Tohoku University Hospital, Miyagi, Japan.
3
Division of Pathology, Miyagi Cancer Center, Miyagi, Japan.
4
Department of Cancer Biology, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan.
5
Department of Biological Science, Graduate School of Humanities and Sciences, Nara Women's University, Nara, Japan.
6
Division of Cancer Molecular Biology, Tohoku University School of Medicine, Miyagi, Japan.

Abstract

Here, we address the function of protein phosphatase 6 (PP6) loss on K-ras-initiated tumorigenesis in keratinocytes. To do so, we developed tamoxifen-inducible double mutant (K-rasG12D -expressing and Ppp6c-deficient) mice in which K-rasG12D expression is driven by the cytokeratin 14 (K14) promoter. Doubly-mutant mice showed early onset tumor formation in lips, nipples, external genitalia, anus and palms, and had to be killed by 3 weeks after induction by tamoxifen, while comparably-treated K-rasG12D -expressing mice did not. H&E-staining of lip tumors before euthanasia revealed that all were papillomas, some containing focal squamous cell carcinomas. Immunohistochemical analysis of lips of doubly-mutant vs K-rasG12D mice revealed that cell proliferation and cell size increased approximately 2-fold relative to K-rasG12D -expressing mutants, and epidermal thickness of lip tissue greatly increased relative to that seen in K-rasG12D -only mice. Moreover, AKT phosphorylation increased in K-rasG12D -expressing/Ppp6c-deficient cells, as did phosphorylation of the downstream effectors 4EBP1, S6 and GSK3, suggesting that protein synthesis and survival signals are enhanced in lip tissues of doubly-mutant mice. Finally, increased numbers of K14-positive cells were present in the suprabasal layer of doubly-mutant mice, indicating abnormal keratinocyte differentiation, and γH2AX-positive cells accumulated, indicating perturbed DNA repair. Taken together, Ppp6c deficiency enhances K-rasG12D -dependent tumor promotion.

KEYWORDS:

AKT pathway; K-ras; mouse keratinocyte; protein phosphatase 6; tumor initiation and promotion

PMID:
29758119
PMCID:
PMC6029815
DOI:
10.1111/cas.13638
[Indexed for MEDLINE]
Free PMC Article

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