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.

Human microRNA expression in sporadic and FAP-associated desmoid tumors and correlation with beta-catenin mutations

“…These results are consistent with the in vitro experiments reported by Lin et al [25] who demonstrated that over-expressed miR-21-5p (opposite arm of the miR-21-3p) in colorectal cancer cell lines promoted β-catenin nuclear translocation via increased phosphorylation of this protein at Serine552 and this phenomenon was associated with mutated CTNNB1 gene.…”

ICAT inhibits glioblastoma cell proliferation by suppressing Wnt/β-catenin activity

“…The translocation of β-catenin is a key molecular event in tumor formation [19]. In colorectal cancer, due to a mutation in the APC tumor suppressor gene, β-catenin accumulates and translocates into the nucleus.…”

XRCC1 Gene Polymorphisms and miR-21 Expression in Patients with Colorectal Carcinoma

“…Huang et al [3] is involved in the development of malignant tumors through its effects on cell apoptosis, proliferation, invasion, and metastasis by targeting phosphatase, tensin homolog (PTEN), and tissue inhibitor of metalloproteinases 3 (TIMP3) or through its role in signaling pathways such as Wnt/β-catenin, PTEN/PI-3K/AKT, and RAS/ MEK/ERK [6,7]. Recent studies showed that miR-21 is frequently up-regulated in CRC and that elevated expression of miR-21 is associated with worse prognosis and inefficient response to chemotherapy [8,9]. Moreover, Li et al [10] found that knocking down miR-21 expression in the CRC cell line SW-480 suppressed the invasion, migration, and proliferation of the cells.…”