| First Author | Kurosawa K | Year | 2018 |
| Journal | Cancer Sci | Volume | 109 |
| Issue | 7 | Pages | 2178-2187 |
| PubMed ID | 29758119 | Mgi Jnum | J:273924 |
| Mgi Id | MGI:6282860 | Doi | 10.1111/cas.13638 |
| Citation | Kurosawa K, et al. (2018) Loss of protein phosphatase 6 in mouse keratinocytes enhances K-ras(G12D) -driven tumor promotion. Cancer Sci 109(7):2178-2187 |
| abstractText | 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-ras(G12D) -expressing and Ppp6c-deficient) mice in which K-ras(G12D) 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-ras(G12D) -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-ras(G12D) mice revealed that cell proliferation and cell size increased approximately 2-fold relative to K-ras(G12D) -expressing mutants, and epidermal thickness of lip tissue greatly increased relative to that seen in K-ras(G12D) -only mice. Moreover, AKT phosphorylation increased in K-ras(G12D) -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 gammaH2AX-positive cells accumulated, indicating perturbed DNA repair. Taken together, Ppp6c deficiency enhances K-ras(G12D) -dependent tumor promotion. |
