CircWDR37 promotes hepatocellular carcinoma tumorigenesis by mediating the miR-646/TRAF4 regulatory pathway

Abstract

Background

CircRNA has emerged as a significant player in human malignancies, including hepatocellular carcinoma (HCC). Hsa_circ_0004277 (circWDR37) is abnormally up-regulated in HCC. But, its function and underlying mechanism in HCC progression are largely unknown.

Methods

qRT-PCR and western blot assays were used to measure the expression of circWDR37, miR-646, and TRAF4. Cell malignant phenotypes were assessed via CCK-8, EdU, colony formation, flow cytometry, transwell, and tube formation experiments. The intermolecular interaction between miR-646 and circWDR37 or TRAF4 was confirmed by dual-luciferase reporter and RNA immunoprecipitation (RIP) assay. The in vivo effect of circWDR37 on xenograft tumor growth was also investigated in mice.

Results

Increased CircWDR37 and TRAF4 and decreased miR-646 were found in HCC tissues and cells. Scilencing circWDR37 impeded cell proliferation, migration, invasion, and tube formation, while accelerated apoptosis. CircWDR37 directly bind to miR-646 to suppress miR-646 expression and up-regulate TRAF4 expression. MiR-646 inhibitor partially abated the cell phenotype changes caused by circWDR37 knockdown. Moreover, miR-646 exerted an inhibitory effect on cell malignant phenotypes, which were attenuated due to the increase of TRAF4. Additionally, circWDR37 knockdown blocked HCC tumor growth in vivo.

Conclusion

CircWDR37 exerted an oncogenic effect in HCC by sponging miR-646 to up-regulate TRAF4 expression. Our finding elucidates a novel ‘circWDR37-miR-646-TRAF4’ regulatory axis in HCC and provides a promising target for HCC treatment.