Inhibition of the aberrant A1CF-FAM224A-miR-590-3p-ZNF143 positive feedback loop attenuated malignant biological behaviors of glioma cells

Background: Glioma is the most common and lethal type of malignant brain tumor. Accumulating evidence has highlighted that RNA binding protein APOBEC1 complementation factor (A1CF) is involved in various cellular processes by modulating RNA expression, and acts as an oncogene in breast cancer. However, the function of A1CF in glioma remained unclear.

Methods: Quantitative RT-PCR and western blot analysis were employed to detect the expression levels of A1CF, lncRNA family with sequence similarity 224 member A (FAM224A), miR-590-3p, zinc finger protein 143 (ZNF143) and ArfGAP with SH3 domain, ankyrin repeat and PH domain 3 (ASAP3) in glioma tissues and cell lines. The Cell Counting Kit-8 assay, migration and invasion assays, and flow cytometry analysis were conducted to evaluate the function of A1CF, FAM224A, miR-590-3p, ZNF143 and ASAP3 in the malignant biological behaviors of glioma cells. Moreover, luciferase reporter, RIP and ChIP assays were used to investigate the interactions among A1CF, FAM224A, miR-590-3p, ZNF143, ASAP3 and MYB. Finally, the xenograft tumor growth assay further ascertained the biological roles of A1CF, FAM224A and miR-590-3p in glioma cells.

Results: A1CF was upregulated and functioned as an oncogene via stabilizing and increasing FAM224A expression; moreover, high A1CF and FAM224A expression levels indicated a poorer prognosis for glioma patients. Conversely, miR-590-3p was downregulated and exerted a tumor-suppressive function in glioma cells. Inhibition of A1CF significantly restrained cell proliferation, migration and invasion, and promoted apoptosis by upregulating miR-590-3p in a FAM224A-dependent manner. FAM224A was a molecular sponge of miR-590-3p and they were in an RNA-induced silencing complex. ZNF143 was upregulated in glioma tissues and cell lines. MiR-590-3p could negatively modulate the expression of ZNF143 via binding to the ZNF143 3' UTR. Moreover, ZNF143 participated in miR-590-3p-induced tumor-suppressive activity on glioma cells. ASAP3 and MYB were transcriptionally activated by ZNF143, and importantly, ZNF143 could directly target the promoter of FAM224A and stimulate its expression, collectively forming a positive feedback loop.

Conclusions: The present study clarifies that the A1CF-FAM224A-miR-590-3p-ZNF143 positive feedback loop conducts critical regulatory effects on the malignant progression of glioma cells, which provides a novel molecular target for glioma therapy.