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

Liang, Wei-Cheng, Wong, Cheuk-Wa, Liang, Pu-Ping, Shi, Mai, Cao, Ye, Rao, Shi-Tao, Tsui, Stephen Kwok-Wing, Waye, Mary Miu-Yee, Zhang, Qi, Fu, Wei-Ming, Zhang, Jin-Fang
Genome biology 2019 v.20 no.1 pp. 84
amino acids, beta catenin, cell growth, circular RNA, cytoplasm, eukaryotic cells, gene expression, hepatoma, loci, messenger RNA, neoplasm cells, phenotype, phosphorylation, protein content, start codon, stop codon, tissues, translation (genetics)
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 β-catenin gene locus, circβ-catenin. RESULTS: Circβ-catenin is predominantly localized in the cytoplasm and displays resistance to RNase-R treatment. We find that circβ-catenin is highly expressed in liver cancer tissues when compared to adjacent normal tissues. Silencing of circβ-catenin significantly suppresses malignant phenotypes in vitro and in vivo, and knockdown of this circRNA reduces the protein level of β-catenin without affecting its mRNA level. We show that circβ-catenin affects a wide spectrum of Wnt pathway-related genes, and furthermore, circβ-catenin produces a novel 370-amino acid β-catenin isoform that uses the start codon as the linear β-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 β-catenin by antagonizing GSK3β-induced β-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.