Comprehensive circular RNA profiling reveals the regulatory role of the circRNA-100338/miR-141-3p pathway in hepatitis B-related hepatocellular carcinoma

Xiu-Yan Huang,Zi Chen,Zi-Li Huang,Wei Song,Qi Zheng,Jian Zhou,Yong-Hua Xu,Zhao-You Tang,Xin-Yu Huang

doi:10.1038/s41598-017-05432-8

Abstract

Circular RNAs (circRNAs) represent a class of endogenous noncoding RNAs that have recently been recognized as important regulators of gene expression and pathological networks. However, their transcriptional activities and functional mechanisms in cancer remain largely unknown. Here, we present results from a global circRNA expression and functional analysis of patients with hepatocellular carcinoma (HCC). Using a circRNA microarray, we identified 226 differentially expressed circRNAs, of which 189 were significantly upregulated and 37 were downregulated. High expression of circRNA_100338, one of the upregulated circRNAs in HCC, is closely correlated with a low cumulative survival rate and metastatic progression in HCC patients with hepatitis B. Furthermore, our in silico and experimental analyses identified miR-141-3p as a direct target of circRNA_100338. Thus, circRNA_100338 functions as an endogenous sponge for miR-141-3p in HCC. In addition, we identified the crucial antagonistic roles of circRNA_100338 and miR-141-3p in the regulation of invasive potential in liver cancer cells. Overall, the differential expression of multiple circRNAs in HCC tissues and their clinical significance in hepatitis B-related HCC patients as revealed by our study suggests that circRNA_100338 is a potentially valuable biomarker for HCC diagnosis and target for HCC therapeutics.

Highlights

Circular RNAs represent a class of naturally occurring endogenous noncoding RNAs that have recently been recognized as important regulators of gene expression networks
Recent studies from two independent groups showed that one human circRNA derived from the antisense strand of the human Cerebellar Degeneration-Related protein 1 (CDR1) locus contains more than 70 endogenous miR-7 target recognition sites, thereby serving as a miR-7 sponge to “sponge up” or sequester the biological impacts of endogenous
To increase the reliability of differential expression detected in the microarray between hepatocellular carcinoma (HCC) and paired pericancerous tissues, circRNAs with low signal intensities or not expressed in all samples in the array were first filtered out

Summary

Introduction

Circular RNAs (circRNAs) represent a class of naturally occurring endogenous noncoding RNAs that have recently been recognized as important regulators of gene expression networks. The testis-specific circRNA Sry functions as a miR-138 sponge[4]. These findings suggest that circRNAs play a crucial role in regulating gene expression and that alteration of circRNA expression may contribute to the pathogenesis of many diseases, including cancer. The development of HCC is a complex process that involves accumulation of gene regulation alteration at multiple levels, and molecules such as transcriptional factors, histone modifiers, microRNAs, lncRNAs and ceRNAs have been identified to play adominant role[16,17,18,19,20]. The exact roles of circRNAs in cancer and the underlying molecular mechanism of circRNA-mediated gene regulation during HCC development remain elusive

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Discussion

Conclusion