CircMTO1 suppresses hepatocellular carcinoma progression via the miR-541-5p/ZIC1 axis by regulating Wnt/β-catenin signaling pathway and epithelial-to-mesenchymal transition

• Published in: Cell death & disease 2021-12, Vol.13 (1), p.12-12, Article 12
• Main Authors: Li, Dandan, Zhang, Jiawei, Yang, Jing, Wang, Jie, Zhang, Runling, Li, Jinming, Zhang, Rui
• Format: Article
• Language: English
• Subjects: 13; 13/109; 13/2; 13/31; 38/90; 45/61; 45/77; 631/67/1059; 631/67/1244; 631/67/1504/1610; 64/60; 82/51; Animals; Antibodies; Apoptosis; Apoptosis - genetics; Biochemistry; Bioinformatics; Biomedical and Life Sciences; c-Myc protein; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Biology; Cell Culture; Cell migration; Cell Movement - genetics; Cell proliferation; Cell Proliferation - genetics; Cholecystokinin; Chromosome 5; Cyclin D1; E-cadherin; Epithelial-Mesenchymal Transition - genetics; Gelatinase A; HEK293 Cells; Hep G2 Cells; Hepatocellular carcinoma; Humans; Immunology; Life Sciences; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Mesenchyme; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; Mitochondria; Myc protein; N-Cadherin; RNA, Circular - genetics; RNA, Circular - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Signal transduction; Therapeutic targets; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection - methods; tRNA; Tumor Burden - drug effects; Tumor Burden - genetics; Tumor suppressor genes; Tumors; Vimentin; Wnt protein; Wnt Signaling Pathway - genetics; Xenograft Model Antitumor Assays; β-Catenin
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04464-3

CircRNA mitochondrial tRNA translation optimization 1 (circMTO1) functions as a tumor suppressor usually and is related to the progression of many tumors, including hepatocellular carcinoma (HCC). CircMTO1 is downregulated in HCC as compared to adjacent nontumor tissue, which may suppress the HCC progression by certain signal pathways. However, the underlying signal pathway remains largely unknown. The interactions between circMTO1 and miR-541-5p were predicted through bioinformatics analysis and verified using pull-down and dual-luciferase reporter assays. CCK-8, transwell, and apoptosis assays were performed to determine the effect of miR-541-5p on HCC progression. Using bioinformatic analysis, dual-luciferase reporter assay, RT-qPCR, and western blot, ZIC1 was found to be the downstream target gene of miR-541-5p. The regulatory mechanisms of circMTO1, miR-541-5p, and ZIC1 were investigated using in vitro and in vivo rescue experiments. The results depicted that silencing circMTO1 or upregulating miR-541-5p expression facilitated HCC cell proliferation, migration, and invasion and inhibited apoptosis. CircMTO1 silencing upregulated the expression of downstream ZIC1 regulators of the Wnt/β-catenin pathway markers, β-catenin, cyclin D1, c-myc, and the mesenchymal markers N-cadherin, Vimentin, and MMP2, while the epithelial marker E-cadherin was downregulated. MiR-541-5p knockdown had the opposite effect and reversed the effect of circMTO1 silencing on the regulation of downstream ZIC1 regulators. Intratumoral injection of miR-541-5p inhibitor suppressed tumor growth and reversed the effect of circMTO1 silencing on the promotion of tumor growth in HCC. These findings indicated that circMTO1 suppressed HCC progression via the circMTO1/ miR-541-5p/ZIC1 axis by regulating Wnt/β-catenin signaling and epithelial-to-mesenchymal transition, making it a novel therapeutic target.