Translation of the circular RNA circß-catenin promotes liver cancer cell growth through activation of the Wnt pathway.

ABSTRACT

BACKGROUND: Circular RNAs are a class of regulatory RNA transcripts, which are ubiquitously expressed in eukaryotes. In the current study, we evaluate the function of a novel circRNA derived from the ß-catenin gene locus, circß-catenin. RESULTS: Circß-catenin is predominantly localized in the cytoplasm and displays resistance to RNase-R treatment. We find that circß-catenin is highly expressed in liver cancer tissues when compared to adjacent normal tissues. Silencing of circß-catenin significantly suppresses malignant phenotypes in vitro and in vivo, and knockdown of this circRNA reduces the protein level of ß-catenin without affecting its mRNA level. We show that circß-catenin affects a wide spectrum of Wnt pathway-related genes, and furthermore, circß-catenin produces a novel 370-amino acid ß-catenin isoform that uses the start codon as the linear ß-catenin mRNA transcript and translation is terminated at a new stop codon created by circularization. We find that this novel isoform can stabilize full-length ß-catenin by antagonizing GSK3ß-induced ß-catenin phosphorylation and degradation, leading to activation of the Wnt pathway. CONCLUSIONS: Our findings illustrate a non-canonical function of circRNA in modulating liver cancer cell growth through the Wnt pathway, which can provide novel mechanistic insights into the underlying mechanisms of hepatocellular carcinoma.