RESUMEN
Protein Phosphatase 2A (PP2A) enzymes counteract diverse kinase-driven oncogenic pathways and their function is frequently impaired in cancer. PP2A inhibition is indispensable for full transformation of human cells, but whether loss of PP2A is sufficient for tumorigenesis in vivo has remained elusive. Here, we describe spontaneous tumor development in knockout mice for Ppp2r5d, encoding the PP2A regulatory B56δ subunit. Several primary tumors were observed, most commonly, hematologic malignancies and hepatocellular carcinomas (HCCs). Targeted immunoblot and immunohistochemistry analysis of the HCCs revealed heterogeneous activation of diverse oncogenic pathways known to be suppressed by PP2A-B56. RNA sequencing analysis unveiled, however, a common role for oncogenic c-Myc activation in the HCCs, independently underscored by c-Myc Ser62 hyperphosphorylation. Upstream of c-Myc, GSK-3ß Ser9 hyperphosphorylation occurred both in the HCCs and non-cancerous B56δ-null livers. Thus, uncontrolled c-Myc activity due to B56δ-driven GSK-3ß inactivation is the likely tumor predisposing factor. Our data provide the first compelling mouse genetics evidence sustaining the tumor suppressive activity of a single PP2A holoenzyme, constituting the final missing incentive for full clinical development of PP2A as cancer biomarker and therapy target.
Asunto(s)
Carcinogénesis/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Proteína Fosfatasa 2/genética , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinogénesis/patología , Femenino , Genes Supresores de Tumor , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias/patología , Proteína Fosfatasa 2/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Análisis de Secuencia de ARNRESUMEN
Esthetic reconstruction of large-volume Class III ridge deformities where bone and soft tissue have been lost buccolingually as well as apicocoronally continues to offer a major challenge in therapy to periodontists and to those engaged in advanced reconstructive dentistry. No single procedure is well suited for solving all problems in reconstructive surgery. A series of staged surgical procedures is frequently necessary to augment the ridge to its former dimensions. The authors have devised a combination onlay-interpositional graft procedure that appears to offer promise in solving many of the problems encountered in gaining predictable soft tissue ridge augmentation in Class III ridge defects.