Reply.

Abstract

We thank for Dr. Wang for his comment on our recent study.1 In this study, we focused on identification of an IL‐6‐induced circular RNA (circRNA)–circRNA derived from gametogenetin binding protein 2 (cGGNBP2) and its biological function in intrahepatic cholangiocarcinoma (ICC). We found that cGGNBP2 could encode the protein cGGNBP2‐184aa and that IL‐6/cGGNBP2‐184aa/signal transducer and activator of transcription 3 formed a positive feedback loop to facilitate ICC progression. We agree that the cellular roles of circRNA are complex: modulating transcription; regulating splicing, platforms, or sponges for proteins and sponges for microRNAs (miRNAs); interacting with mRNAs; and translating proteins.2,3 Through reviewing the published works concerning the biological functions of circRNAs, most of the known circRNAs were identified as sponges for miRNAs. By stating “Most circRNAs have been proposed to function as a microRNA sponge or protein scaffold,” we did not mean that the main function of circRNAs was sponging miRNAs and protein scaffolds. Indeed, binding sites are necessary for miRNA sponging. In our study, we focused on the translational capability of cGGNBP2 and did not detect the miRNA binding sites. As shown in the paper, we have demonstrated that cGGNBP2 exerts its biological function mainly by translating the protein cGGNBP2‐184aa. Overexpression of cGGNBP2‐184aa markedly increased the growth and invasive capability of ICC cells. However, overexpression of internal ribosome entry site–mutated vectors (by which cGGNBP2 RNA levels could be dramatically elevated, while cGGNBP2‐184aa could not) did not influence the function of ICC cells. This suggested partly that cGGNBP2 might not exert its biological function by sponging miRNAs or proteins. However, further work should be performed to confirm this. In conclusion, we appreciate the comment by Dr. Wang that a comprehensive work should be performed when we discuss the biological function of circRNAs as miRNA sponges.