MicroRNA-21 promotes tumour malignancy via increased nuclear translocation of β-catenin and predicts poor outcome in APC-mutated but not in APC-wild-type colorectal cancer

Abstract

MiR-21 has been associated with poor prognosis in colon adenocarcinomas. However, in our preliminary data, the prognostic value of miR-21 levels was observed only in adenomatous polyposis coli (APC)-mutated tumours, not in APC-wild-type tumours. We explored whether β-catenin nuclear translocation was synergistically promoted by miR-21 in APC-mutated cells but not in APC-wild-type cells. We enrolled 165 colorectal tumour to determine APC mutation, miR-21 levels and nuclear β-catenin expression by direct sequencing, real-time PCR and immunohistochemistry. Overall survival and relapse-free survival were analysed by Kaplan-Meier and Cox regression models. The mechanistic action of β-catenin nuclear translocation modulated by miR-21 and its effect on cell invasion were evaluated in a cell model. Positive nuclear β-catenin expression was more commonly occurred in APC-mutated tumours than in APC-wild-type tumours. High miR-21 levels were relatively more common in tumours with positive nuclear β-catenin expression than in those with negative nuclear β-catenin expression. APC-mutated tumours with high miR-21 levels had shorter overall survival and relapse-free survival periods compared with others. However, the prognostic value of miR-21 levels was not observed in APC-wild-type tumours. Phosphorylation of β-catenin at Ser552 via the miR-21-mediated PTEN/AKT axis plays a critical role in β-catenin nuclear translocation in APC-mutated cells but not in APC-wild-type cells. Moreover, nuclear β-catenin expression increased by miR-21 is responsible for the capability of invasiveness. In summary, nuclear translocation of β-catenin increased by miR-21 promotes tumour malignancy and a poor outcome in APC-mutated patients but not in APC-wild-type colorectal cancer.