Paclitaxel Suppresses Hepatocellular Carcinoma Tumorigenesis Through Regulating Circ-BIRC6/miR-877-5p/ YWHAZ Axis

摘要

Background: Paclitaxel is an effective chemotherapeutic agent for the treatment of cancer patients. Accumulating evidence suggests that circular RNAs (circRNAs) play critical roles in the occurrence and development of human cancers. However, there are few studies on interactions between paclitaxel and circRNAs in hepatocellular carcinoma (HCC). Materials and Methods: Cell counting kit-8 (CCK-8) assay and colony formation assay were conducted to determine cell proliferation. Cell apoptosis was assessed by flow cytometry. The expression levels of circRNA baculoviral IAP repeat-containing 6 (circ-BIRC6), microRNA-877-5p (miR-877-5p), and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta ( YWHAZ ) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The mice xenograft model was established to investigate the roles of circ-BIRC6 and paclitaxel in vivo. The interaction between miR-877-5p and circ-BIRC6 or YWHAZ was predicted by bioinformatics analysis and verified by dual-luciferase reporter assay. Western blot assay was applied for measuring the protein expression of YWHAZ. Results: Paclitaxel suppressed HCC tumorigenesis through decreasing cell proliferation and accelerating apoptosis. Circ-BIRC6 and YWHAZ were upregulated, and miR-877-5p was downregulated in HCC tissues and cells. Paclitaxel treatment inhibited the expression of circ-BIRC6 and YWHAZ while promoted the expression of miR-877-5p. Circ-BIRC6 overexpression or miR-877-5p interference reversed the inhibitory effect of paclitaxel on HCC tumorigenesis. Moreover, miR-877-5p could specially bind to YWHAZ , and its knockdown abated the suppressive effect of circ-BIRC6 depletion on HCC tumorigenesis. Additionally, YWHAZ was identified as a direct target of miR-877-5p. Besides, circ-BIRC6 functioned as a molecular sponge of miR-877-5p to regulate YWHAZ expression. Conclusion: Paclitaxel limited HCC tumorigenesis via modulating circ-BIRC6/miR-877-5p/ YWHAZ axis, providing a novel therapeutic approach for the treatment of HCC.