CircRNA-100338 Is Associated With mTOR Signaling Pathway and Poor Prognosis in Hepatocellular Carcinoma

Ping-Bao Zhang,Jian Zhou,Zi-Li Huang,Hong-Cheng Wang,Xiu-Yan Huang,Zhao-You Tang,Bin Xu,Xin-Yu Huang,Jin Huang

doi:10.3389/fonc.2019.00392

Abstract

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide. Despite advances in the diagnosis and treatment of HCC, incidence, and mortality continue to rise. For accurate diagnosis and treatment of HCC, there is an urgent need to precisely understand the molecular mechanisms underlying HCC tumorigenesis and progression. Accumulating evidence showed that circRNAs, which are normally produced by scrambling of exons at the splicing process, are recognized as a novel class of endogenous noncoding RNA, which have microRNA sponging properties. In this study, we aim to investigate the circRNA-100338 mediated downstream pathway, and evaluate its association with clinicopathological parameters. Integrated analysis of circRNA-100338, miR-141-3p, and target genes revealed that RHEB, a key regulator in mTOR signaling pathway, was the target of miR-141-3p in hepatitis B-related HCC. CircRNA-100338 regulates the activity of mTOR signaling pathway in vitro. IHC analysis revealed that mTOR signaling pathway was more active in HCC tissues with elevated circRNA-100338 expression. These results indicated that circRNA-100338 could regulate mTOR signaling pathway through circRNA-100338/miR-141-3p/RHEB axis. Finally, correlation analysis of RHEB and EIF5 expression with clinicopathological parameters of HCC patients revealed that the circRNA-100338, RHEB, and EIF5 were indicators of poor prognosis in hepatitis B-related HCC. In conclusion, elevated circRNA-100338 activates mTOR signaling pathway in HCC via circRNA-100338/miR-141-3p/RHEB axis and associates with poor prognosis of hepatitis B-related HCC patients.

Highlights

Hepatocellular carcinoma (HCC) is the leading cause of cancerrelated deaths worldwide [1]
It has been reported that circRNA-100338 has the potential to act as a competing endogenous RNA by competing miR-141-3p with mRNAs by our previous study [26], the target genes regulated by circRNA-100338/miR-141-3p in HCC were still unknown
We only identified RHEB (Ras homolog enriched in brain) as the target of miR141-3p in HCC (Figure 2A, Spearman correlation coefficient < −0.6), suggesting that circRNA-100338 may act as a competing endogenous RNA (ceRNA) by competing with RHEB

Summary

Introduction

Hepatocellular carcinoma (HCC) is the leading cause of cancerrelated deaths worldwide [1]. Despite advances in the diagnosis and treatment of HCC, incidence and mortality continue to rise. For accurate diagnosis and treatment of HCC, there is an urgent need to precisely understand the molecular mechanisms underlying HCC tumorigenesis and progression. Sorafenib is approved as one of the few available targeted drugs recommended by definitive guides in clinical practice [3, 4] for advanced HCC, it is still limited in improving the overall survival of HCC patients [5, 6]. Other targeted drugs, such as sunitinib [7], brivanib [8], and everolimus [9], have been tested in clinical trials in the late years, but all failed in the third phase [10]

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