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.
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.
Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung 402, Taiwan.
Po-Lin
PL
Lin
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 115, Taiwan.
De-Wei
DW
Wu
Department of Medicine, Chung Shan Medical University, Taichung 402, Taiwan and Department of Surgery, Chung Shan Medical University Hospital, Taichung 402, Taiwan.
Chi-Chou
CC
Huang
Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung 402, Taiwan.
Tsung-Ying
TY
He
Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung 402, Taiwan, Department of Medicine, Chung Shan Medical University, Taichung 402, Taiwan and Department of Surgery, Chung Shan Medical University Hospital, Taichung 402, Taiwan.
Ming-Chih
MC
Chou
Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung 402, Taiwan.
Gwo-Tarng
GT
Sheu
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 115, Taiwan, hl@tmu.edu.tw.
Huei
H
Lee
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D021381:Protein Transport; D012694:Serine / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D051176:beta Catenin; D012694:Serine