CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1

Junjie Xu,Xiao Liang,Xiaomin Song,Ren-An Jin,Lin Ji,Xiujun Cai,Kirill Gorshkov,Jiang Chen,Wei Zheng,Zhe Wan,Qiming Sun,Yuelong Liang,Xueyong Zheng,Hui Lin

doi:10.1038/s41392-020-00375-5

Abstract

Sorafenib is the first-line chemotherapeutic therapy for advanced hepatocellular carcinoma (HCC). However, sorafenib resistance significantly limits its therapeutic efficacy, and the mechanisms underlying resistance have not been fully clarified. Here we report that a circular RNA, circRNA-SORE (a circular RNA upregulated in sorafenib-resistant HCC cells), plays a significant role in sorafenib resistance in HCC. We found that circRNA-SORE is upregulated in sorafenib-resistant HCC cells and depletion of circRNA-SORE substantially increases the cell-killing ability of sorafenib. Further studies revealed that circRNA-SORE binds the master oncogenic protein YBX1 in the cytoplasm, which prevents YBX1 nuclear interaction with the E3 ubiquitin ligase PRP19 and thus blocks PRP19-mediated YBX1 degradation. Moreover, our in vitro and in vivo results suggest that circRNA-SORE is transported by exosomes to spread sorafenib resistance among HCC cells. Using different HCC mouse models, we demonstrated that silencing circRNA-SORE by injection of siRNA could substantially overcome sorafenib resistance. Our study provides a proof-of-concept demonstration for a potential strategy to overcome sorafenib resistance in HCC patients by targeting circRNA-SORE or YBX1.

Highlights

Hepatocellular carcinoma (HCC) is the most common primary liver tumor with an increasing global incidence
We found that circRNA_104797, which we renamed as circRNA-SORE
CircRNA-SORE is overexpressed in sorafenib-resistant HCC cells Increasing evidence has indicated the involvement of circRNAs in various cancer-related processes

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most common primary liver tumor with an increasing global incidence. A previous study showed that sorafenib prolonged the median overall survival (OS) by 2.3−3 months in advanced HCC patients that did not qualify for liver transplantation or resection.[2] many HCC patients respond poorly to sorafenib or develop resistance after months of treatment.[3] Sorafenib resistance in HCC is usually observed within 6 months of treatment.[4] Compelling evidence has suggested that the primary and acquired resistance of sorafenib in HCC involves multiple mechanisms, including autophagy, epithelial−mesenchymal transition, cancer stem cells, tumor microenvironment, and epigenetic regulation, and a number of signaling pathways are suggested to be involved, such as Wnt/β-catenin, TGFβ, Ras/MEK/ERK, PI3K/Akt, TNFα/NF-κB, and JAK/STAT pathways.[4] the mechanisms of sorafenib resistance, in vivo and in HCC patients, have not been well studied and remain poorly understood

Methods

Results

Conclusion