The aberrant activation of the Wnt pathway caused by beta-catenin mutation and its prognostic significance in NK/T-cell lymphoma

摘要

The aberrant activation of the Wnt/beta-catenin signal has an important role in the progression of cancers. Herein, we investigated beta-catenin mutation and the activation of the Wnt pathway in association with the clinical-pathological characteristics, chemo-resistance and prognosis of NK/T-cell lymphoma (NKTCL). Real-time quantitative PCR, immunocytochemistry and immunohistochemistry SP methods detected the levels of beta-catenin, c-myc and cyclin D1 in human NKTCL cell lines (SNK-6 and YTS) and NKTCL tissues. Mutation analysis was detected in exon 3 of beta-catenin gene; and we analyzed cell viability after histone deacetylase inhibitor (HDACi) treatment. As a result, 19 (38%) of NK/T-cell lymphoma displayed nuclear beta-catenin and 16 (32%) contained mutations in exon 3; while no mutations were detected in lymphomas negative for beta-catenin nuclear staining (p<0.05). Most mutations affecting beta-catenin were adjacent to regulatory phosphorylation sites. beta-catenin, c-myc and cyclin D1 were significantly elevated in SNK-6 and YTS cell lines compared to normal NK/T cells (p<0.05). Furthermore, the high expression of beta-catenin, c-myc and cyclin D1 significantly correlated with the III/IV Ann Arbor stage. Additionally, the expression of beta-catenin in the SNK-6 cell line decreased significantly after treatment with HDACi, and Kaplan-Meier survival analysis revealed that the elevated expression of beta-catenin correlated with poor prognosis in NKTCL patients (23.66 +/- 2.77 months vs 31.65 +/- 1.78 months, p=0.023). In conclusion: mutations in exon 3 of beta-catenin and the activated Wnt pathway are common in NK/T-cell lymphoma that has nuclear beta-catenin, and it is closely correlated with the Ann Arbor stage and prognosis in NKTCL patients.