The WIP1 oncogene promotes progression and invasion of aggressive medulloblastoma variants

Abstract

Recent studies suggest that medulloblastoma, the most common malignant brain tumor of childhood, is comprised of four disease variants. The WIP1 oncogene is overexpressed in Group 3 and 4 tumors, which contain medulloblastomas with the most aggressive clinical behavior. Our data demonstrate increased WIP1 expression in metastatic medulloblastomas, and inferior progression-free and overall survival of patients with WIP1 high-expressing medulloblastoma. Microarray analysis identified up-regulation of genes involved in tumor metastasis, including the G protein-coupled receptor CXCR4, in medulloblastoma cells with high WIP1 expression. Stimulation with the CXCR4 ligand SDF1ααactivated PI-3 kinase signaling, and promoted growth and invasion of WIP1 high-expressing medulloblastoma cells in a p53-dependent manner. When xenografted into the cerebellum of immunodeficient mice, medulloblastoma cells with stable or endogenous high WIP1 expression exhibited strong expression of CXCR4 and activated AKT in primary and invasive tumor cells. WIP1 or CXCR4 knock-down inhibited medulloblastoma growth and invasion. WIP1 knock-down also improved the survival of mice xenografted with WIP1 high-expressing medulloblastoma cells. WIP1 knock-down inhibited cell surface localization of CXCR4 by suppressing expression of the G protein receptor kinase 5, GRK5. Restoration of wild-type GRK5 promoted Ser339 phosphorylation of CXCR4 and inhibited the growth of WIP1-stable medulloblastoma cells. Conversely, GRK5 knock-down inhibited Ser339 phosphorylation of CXCR4, increased cell surface localization of CXCR4, and promoted the growth of medulloblastoma cells with low WIP1 expression. These results demonstrate cross-talk among WIP1, CXCR4, and GRK5, which may be important for the aggressive phenotype of a subclass of medulloblastomas in children.

Phosphatase Wip1 as a new therapeutic target for intestinal ischemia-reperfusion injury

“…Phosphatase Wip1 has long been recognized as an oncogene in tumorigenesis because of its overexpression in human tumors, as well as the phenomenon of tumor-resistant Wip1-deficient mice [34]. Emerging evidence also highlights the importance of Wip1 in regulating stress-induced and DNA-damage-induced pathways [35].…”

Wip1 knockout inhibits the proliferation and enhances the migration of bone marrow mesenchymal stem cells

“…Wip1 dephosphorylates multiple target proteins, including p53 [8], p38 [9], Chk1/2 [8,10], ATM [11], and AKT [12], in response to various stresses, tumorigenesis and aging [13]. Due to its ability to regulate stress signaling pathways and inflammatory cytokine production, Wip1 has been shown to overcome oncogenic stress-mediated growth arrest [14] and to maintain homeostasis in intestinal stem cells [15].…”

Phosphatase Wip1 Masters IL-17–producing Neutrophil-mediated Colitis in Mice

“…It is worthwhile to note that Wip1 is emerging as an important oncogene because of its role in regulating several key tumor suppressor pathways and is believed to be a promising drug target for cancer therapy. 47,48 This study suggests that Wip1 inhibitors might simultaneously increase the severity of IBD during their applications to treat cancers. However, increasing Wip1 expression may be used to treat IBD in the future.…”