circ-BIRC6, a circular RNA, promotes hepatocellular carcinoma progression by targeting the miR-3918/Bcl2 axis

Circular (circ)RNA is a special type of endogenous RNA consisting of a covalently closed loop structure without 5‘ to 3‘ polarity and a polyadenylated tail. Accumulating evidence suggests that circRNAs play important roles in the development and progression of human cancers. However, the role of circRNAs in the progression of hepatocellular carcinoma (HCC) is largely unknown. This was addressed in the present study using high-throughput sequencing to identify aberrantly expressed circRNAs in HCC patient tissue and cell lines. We found that circ-baculoviral IAP repeat-containing (BIRC)6 was upregulated in HCC tissue samples and cells; this was associated with the overall survival of HCC patients. circ-BIRC6 knockdown reduced HCC cell proliferation, migration, and invasion and enhanced their apoptosis. Additionally, circ-BIRC6 overexpression negatively regulated the expression of microRNA miR-3918, which was identified as an inhibitor of B cell lymphoma (Bcl)2. The tumor-suppressive effect of circ-BIRC6 deletion was abrogated by inhibiting miR-3918. These results indicate that circ-BIRC6 functions as a competing endogenous RNA that regulates Bcl2 expression by sponging miR-3918, and may serve as a prognostic biomarker and therapeutic target for the treatment of HCC.

环状RNA（circular RNA, circRNA）是一类特殊的内源性RNA，具有共价闭合的环状结构，无5'至3'极性及多腺苷酸化尾。越来越多的研究证据表明，circRNA在人类癌症的发生与进展中发挥关键作用。然而，circRNA在肝细胞癌（hepatocellular carcinoma, HCC）进展中的作用仍未被充分阐明。本研究通过高通量测序技术，筛选肝癌患者组织及细胞系中的异常表达circRNA，对该问题展开了系统探究。研究发现，环状杆状病毒IAP重复序列包含蛋白6（circ-BIRC6，对应基因为baculoviral IAP repeat-containing, BIRC6）在肝癌组织样本与细胞中呈上调表达，且该表达水平与肝癌患者的总生存期显著相关。敲低circ-BIRC6可显著抑制肝癌细胞的增殖、迁移与侵袭，并促进其凋亡。此外，circ-BIRC6过表达可负调控微小RNA（microRNA）miR-3918的表达，而miR-3918被证实为B细胞淋巴瘤-2（B cell lymphoma, Bcl2）的抑制剂。抑制miR-3918可抵消circ-BIRC6敲除所产生的抑瘤效应。上述结果表明，circ-BIRC6可作为内源竞争RNA（competing endogenous RNA, ceRNA），通过海绵吸附miR-3918调控Bcl2的表达，有望成为肝癌预后生物标志物及潜在治疗靶点。