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

Abstract

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.

CircLIFR suppresses hepatocellular carcinoma progression by sponging miR-624-5p and inactivating the GSK-3β/β-catenin signaling pathway

“…For example, circMTO1 is downregulated in HCC tumor tissues, and is associated with favorable OS of HCC patients. Its role may be to act as a sponge for miR-9-5p, thus increasing the expression of P21 and NOX4 [ 7 , 8 ]. Researchers have demonstrated that circ-TCF4.85 is upregulated in patients with HCC and promotes HCC progression by targeting miR-486-5p [ 9 ].…”

RNA-sep analysis of circular RNAs and ceRNA networks in human hepatocellular carcinoma

“…An increasing number of experiments have demonstrated that circRNAs can promote the development of HCC by regulating various signals involved with the cell cycle, proliferation, differentiation, cell survival and apoptosis, leading to abnormal activation of several molecules in signal transduction pathways [18] . Studies have con rmed that circRNAs can act via the AKT/ERK [19] , Wnt/βcatenin [20] , nuclear factor-kappa B [21], hedgehog [22] , c-Met [23] , JAK2/STAT3 [24] and other signalling pathways and are involved in the malignant biological behaviours of HCC. Recent studies have con rmed that circRNAs not only exert biological functions through the above signalling pathways but also affect the biological processes of HCC through other pathways.…”

Circular RNA and Its Roles in the Occurrence, Development, Diagnosis of Cancer

“…For example, cirMAT2B can be combined with miR-515-5p to increase the expression of HIF-1α and promote the growth of gastric cancer ( 32 ). Moreover, circMTO1 can also combine with miR-541-5p to inhibit the progression of liver cancer ( 33 ).…”