N 6 -methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling

Author(s): Junjie Xu ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Zhe Wan ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Minyue Tang ⁶ , Zhongjie Lin ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Shi Jiang ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Lin Ji ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Kirill Gorshkov ⁷ , Qijiang Mao ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Shunjie Xia ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Dong Cen ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Junhao Zheng ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Xiao Liang ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, , Xiujun Cai ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^,

Publication date (Electronic): 23 November 2020

Journal: Molecular Cancer

Publisher: BioMed Central

Keywords: Sorafenib resistance, Hepatocellular carcinoma, Circular RNA, m6A

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Abstract

Background and aims

Accumulating evidence suggests that the primary and acquired resistance of hepatocellular carcinoma (HCC) to sorafenib is mediated by multiple molecular, cellular, and microenvironmental mechanisms. Understanding these mechanisms will enhance the likelihood of effective sorafenib therapy.

Methods

In vitro and in vivo experiments were performed and clinical samples and online databases were acquired for clinical investigation.

Results

In this study, we found that a circular RNA, circRNA-SORE, which is up-regulated in sorafenib-resistant HCC cells, was necessary for the maintenance of sorafenib resistance, and that silencing circRNA-SORE substantially increased the efficacy of sorafenib-induced apoptosis. Mechanistic studies determined that circRNA-SORE sequestered miR-103a-2-5p and miR-660-3p by acting as a microRNA sponge, thereby competitively activating the Wnt/β-catenin pathway and inducing sorafenib resistance. The increased level of circRNA-SORE in sorafenib-resistant cells resulted from increased RNA stability. This was caused by an increased level of N ⁶-methyladenosine (m ⁶A) at a specific adenosine in circRNA-SORE. In vivo delivery of circRNA-SORE interfering RNA by local short hairpin RNA lentivirus injection substantially enhanced sorafenib efficacy in animal models.

Conclusions

This work indicates a novel mechanism for maintaining sorafenib resistance and is a proof-of-concept study for targeting circRNA-SORE in sorafenib-treated HCC patients as a novel pharmaceutical intervention for advanced HCC.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12943-020-01281-8.

Related collections

Most cited references 48

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Circular RNAs are a large class of animal RNAs with regulatory potency.

Sebastian Memczak, Marvin Jens, Antigoni Elefsinioti … (2013)

Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences.

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Natural RNA circles function as efficient microRNA sponges.

Thomas B. Hansen, Trine I. Jensen, Bettina H. Clausen … (2014)

MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.

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Sorafenib in advanced hepatocellular carcinoma.

Josep Llovet, Sergio Ricci, Vincenzo Mazzaferro … (2008)

No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. (ClinicalTrials.gov number, NCT00105443.) 2008 Massachusetts Medical Society

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Author and article information

Contributors

Xiao Liang: srrshlx@zju.edu.cn

Xiujun Cai:

ORCID: http://orcid.org/0000-0002-6457-0577

srrsh_cxj@zju.edu.cn

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 23 November 2020

Publication date PMC-release: 23 November 2020

Publication date Collection: 2020

Volume: 19

Electronic Location Identifier: 163

Affiliations

[1 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Department of General Surgery, Sir Run-Run Shaw Hospital, , Zhejiang University School of Medicine, ; Hangzhou, 310016 China

[2 ]Key Laboratory of Laparoscopic Technology of Zhejiang Province, Hangzhou, China

[3 ]Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, China

[4 ]Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, China

[5 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Zhejiang University Cancer Center, ; Hangzhou, China

[6 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Department of Reproductive Endocrinology, Women’s Hospital, , Zhejiang University School of Medicine, ; Hangzhou, 310006 China

[7 ]GRID grid.429651.d, ISNI 0000 0004 3497 6087, National Center for Advancing Translational Sciences, National Institutes of Health, ; 9800 Medical Center Drive, Bethesda, MD 20892 USA

Author information

Xiujun Cai http://orcid.org/0000-0002-6457-0577

Article

Publisher ID: 1281

DOI: 10.1186/s12943-020-01281-8

PMC ID: 7681956

PubMed ID: 33222692

SO-VID: e6aa7ed1-a9ae-4af5-bd89-3b933dc8db61

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 19 May 2020

Date accepted : 12 November 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81772546

Award ID: 81827804

Award ID: 81902367

Award Recipient : Junjie Xu Xiujun Cai

Funded by: FundRef http://dx.doi.org/10.13039/501100004731, Natural Science Foundation of Zhejiang Province;

Award ID: LQ19H160026

Award Recipient : Junjie Xu

Funded by: Zhejiang Clinical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases

Award ID: 2018E50003

Award Recipient : Xiujun Cai

Funded by: Key Research and Development Project of Zhejiang Province

Award ID: 2018C03083

Award Recipient : Xiujun Cai

Funded by: Hepatobiliary and Pancreatic Cancer Research of Hubei Chen Xiaoping Science and Technology Development Foundation

Award ID: CXPJJH11900001-2019308

Award ID: CXPJJH11900009-03

Award ID: CXPJJH11900001-2019209

Award Recipient : Junjie Xu Xiao Liang

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: sorafenib resistance,hepatocellular carcinoma,circular rna,m6a

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: sorafenib resistance, hepatocellular carcinoma, circular rna, m6a

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