Over-expression of Wild-type p53-induced phosphatase 1 confers poor prognosis of patients with gliomas
Dept. of Neurosurgery, The Second Hospital of Hebei Medical University, China. Brain research
(Impact Factor: 2.84).
03/2012; 1444:65-75. DOI: 10.1016/j.brainres.2011.12.052
Wild-type p53-induced phosphatase 1 (Wip1) is a member of the protein phosphatase 2C family, which is characterized by distinctive oncogenic properties. Overexpression of Wip1 is observed in certain types of human tumors that are associated with significantly poor prognosis. This study aimed to detect the expression of Wip1 in gliomas and to analyze its prognostic value in the patients. Wip1 mRNA and protein expression profiles in 81 gliomas and 15 normal brain tissues were detected using RT-PCR, Western blot and immunohistochemistry. The specimens were stained with proliferating cell nuclear antigen (PCNA) and p53 and evaluated using immunohistochemistry. Detailed clinical and demographic information of patients were retrospectively collected until 5years post-operation. Kaplan-Meier survival and Cox's regression analyses were performed to evaluate the prognosis of patients. Wip1-positive expression was observed in the majority of glioma tissues, whereas no Wip1 expression was detected in the normal brain tissues. Wip1-positive expression significantly correlated with glioma histological grade. The PCNA index was higher in the Wip1-positive group compared to that in the Wip1-negative group. A univariate analysis and log-rank test indicated that statistically significant association between Wip1 expression and the lower overall survival rate in the patients with glioma. A multivariate analysis also indicated a statistically significant association between increased Wip1 expression and lower overall survival rate. Our results suggest that Wip1 may be related to pathological diagnosis and prognosis evaluation for malignant gliomas.
Available from: René H Medema
- "On the other hand, tumors that retain wild-type p53 are likely to accumulate other genetic defects that would allow them to overcome the DDR barrier, providing a growth advantage in the presence of replicative stress. Importantly, amplification of the 17q23 locus carrying the PPM1D gene has been reported in various p53 wild-type tumors, pointing toward a role of Wip1 in cancer development, and Wip1 overexpression is associated with poor prognosis (Bulavin et al., 2002, 2004; Li et al., 2002; Saito-Ohara et al., 2003; Rauta et al., 2006; Castellino et al., 2008; Liang et al., 2012). The oncogenic behavior of Wip1 is further supported by mouse genetics showing that loss of Wip1 protects from cancer development (Bulavin et al., 2004; Nannenga et al., 2006). "
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ABSTRACT: The DNA damage response (DDR) pathway and its core component tumor suppressor p53 block cell cycle progression after genotoxic stress and represent an intrinsic barrier preventing cancer development. The serine/threonine phosphatase PPM1D/Wip1 inactivates p53 and promotes termination of the DDR pathway. Wip1 has been suggested to act as an oncogene in a subset of tumors that retain wild-type p53. In this paper, we have identified novel gain-of-function mutations in exon 6 of PPM1D that result in expression of C-terminally truncated Wip1. Remarkably, mutations in PPM1D are present not only in the tumors but also in other tissues of breast and colorectal cancer patients, indicating that they arise early in development or affect the germline. We show that mutations in PPM1D affect the DDR pathway and propose that they could predispose to cancer.
Available from: Silvia Pandolfi
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ABSTRACT: The Hedgehog-GLI (HH-GLI) signaling plays a critical role in controlling growth and tissue patterning during embryogenesis and is implicated in a variety of human malignancies, including those of the skin. Phosphorylation events have been shown to regulate the activity of the GLI transcription factors, the final effectors of the HH-GLI signaling pathway. Here, we show that WIP1 (or PPM1D), an oncogenic phosphatase amplified/overexpressed in several types of human cancer, is a positive modulator of the HH signaling. Mechanistically, WIP1 enhances the function of GLI1 by increasing its transcriptional activity, nuclear localization and protein stability, but not of GLI2 nor GLI3. We also find that WIP1 and GLI1 are in a complex. Modulation of the transcriptional activity of GLI1 by WIP1 depends on the latter's phosphatase activity and, remarkably, does not require p53, a known WIP1 target. Functionally, we find that WIP1 is required for melanoma and breast cancer cell proliferation and self-renewal in vitro and melanoma xenograft growth induced by activation of the HH signaling. Pharmacological blockade of the HH pathway with the SMOOTHENED antagonist cyclopamine acts synergistically with inhibition of WIP1 in reducing growth of melanoma and breast cancer cells in vitro. Overall, our data uncover a role for WIP1 in modulating the activity of GLI1 and in sustaining cancer cell growth and cancer stem cell self-renewal induced by activation of the HH pathway. These findings open a novel therapeutic approach for human melanomas and, possibly, other cancer types expressing WIP1 and with activated HH pathway.Oncogene advance online publication, 12 November 2012; doi:10.1038/onc.2012.502.
Available from: ocean.kisti.re.kr
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To investigate the level of expression of proto-oncogene Wip1 and its physiological significance in colorectal cancer.
Immunohistochemistry, semi-quantitative RT-PCR, and Western blotting were used to analyze Wip1 mRNA and protein expression in 120 cases of colorectal cancer and normal tissues to study relationships with clinical symptoms and disease prognosis.
The level of Wip1 protein expression was found to be significantly higher in colorectal cancer tissues (85% (102/120)) than in normal tissues (30% (36/120)) (P < 0.05). The relative amount of Wip1 protein in colorectal cancer tissue was also found to be significantly higher (P < 0.05) than in normal tissues (1.060±0.02 and 0.640±0.023, respectively). Semi-quantitative RT-PCR showed average Wip1 mRNA expression levels to be 1.113 ±0.018 and 0.658±0.036 for colorectal cancer tissue and adjacent normal tissue (P < 0.05). The level of Wip1 protein expression was not correlated with age, gender, or tumor site, but appeared linked with lymph node metastasis, Dukes stage, histological grade, and liver metastasis. Individuals with high and low levels of Wip1 expression showed statistically significant differences in the five-year overall survival and recurrence-free survival rates (P < 0.05).
Wip1 mRNA and protein are highly expressed in colorectal cancers and may be associated with colorectal cancer development and progression.
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