Wnt/beta-Catenin pathway in human glioma: expression pattern and clinical/prognostic correlations

Abstract

Gliomas are the most common primary intracranial tumors. Understanding the molecular basis of gliomas' progression is required to develop more effective therapies. The Wnt/β-catenin signaling cascade is an important signal transduction pathway in human cancers. Although, overactivation of this pathway is a hallmark of several forms of cancer, little is known about its role in human gliomas. Here, we aimed to determine the clinical significance of Wnt/β-catenin pathway components in gliomas. Immunohistochemical staining was performed to detect the expression patterns of Wnt1, β-catenin and Cyclin D1 in the biopsies from 96 patients with primary gliomas. Kaplan-Meier survival and Cox regression analyses were performed to evaluate the prognosis of patients. Cytoplasmic staining pattern of Wnt1, membranous, cytoplasmic and nuclear accumulation of β-catenin, and nuclear localization of Cyclin D1 were demonstrated by immunohistochemical staining. The Wnt1 expression significantly correlated with the expression of Cyclin D1 (P < 0.0001). The ratio of tumors with a cytoplasmic-nuclear pattern or a cytoplasmic pattern of β-catenin was significantly higher in Wnt1-positive (P < 0.01) and Cyclin D1-positive (P < 0.01) tumors than in Wnt1-negative and Cyclin D1-negative tumors, respectively. The protein expression levels of Wnt1, β-catenin and Cyclin D1 were all positively correlated with the Karnofsky performance scale (KPS) score and World Health Organization (WHO) grades of patients with gliomas. Furthermore, Wnt1, cytoplasmic-nuclear β-catenin and Cyclin D1 status were all the independent prognostic factors for glioma patients (P = 0.01, 0.007 and 0.005, respectively). These results provide convincing evidence that the Wnt/β-catenin pathway correlated closely with the progression of gliomas and might be a novel prognostic marker for this neoplasm.

Promoter methylation of WNT inhibitory factor-1 and expression pattern of WNT/β-catenin pathway in human astrocytoma: pathologic and prognostic correlations

“…In contrast, as presented in many studies, cytoplasmic accumulation is observed in a significantly higher proportion of malignant tumors than of normal or nonneoplastic tissue. 4,[26][27][28] This method of grouping actually revealed significant correlation between b-catenin and other markers such as cyclin D1, c-myc, APC, E2F1, p53, and MDM2, and tumor grade and patient survival. 4,26,27 The b-catenin expression in the cytoplasm and/or nucleus could be considered to be an indication of its aberrant expression.…”

“…On the other hand, the reduced level of WIF1 protein expression, more frequent cytoplasmic or cytoplasmic/nuclear b-catenin staining pattern, and increased cyclin D1 and c-myc expression in glioblastomas relative to diffuse astrocytomas were consistent with results of other studies. 2,4,7,25 These findings suggest that WIF1 promoter methylation is a common process that occurs relatively upstream in tumorigenesis, and that the accumulation of additional downstream alterations in the WNT/b-catenin pathway is related to the aggressiveness of astrocytoma.…”

“…4 They are also higher in high ¼ grade tumors than in low-grade tumors. 2,4 Moreover, cytoplasmic/nuclear b-catenin and …”

“…Recently, several reports showed a relationship between the WNT signaling pathway and the grade and prognosis of astrocytomas. [2][3][4] Both mRNA and protein expression levels of b-catenin are increased in astrocytoma compared with normal brain tissue. 4 They are also higher in high ¼ grade tumors than in low-grade tumors.…”

“…2 WNT inhibitory factor-1 (WIF1) is an antagonist that inhibits the WNT signaling pathway; [5][6][7] therefore, functional loss of WIF1 can contribute to tumorigenesis by activation of the WNT pathway. Downregulation of WIF1 mRNA and protein expression levels as a result of WIF1 gene promoter methylation has been reported in human astrocytoma.…”