The circRNA circAGFG1 acts as a sponge of miR-195-5p to promote triple-negative breast cancer progression through regulating CCNE1 expression

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Abstract

Background

In recent years, circular RNAs (circRNAs), a new star of non-coding RNA, have been emerged as vital regulators and gained much attention for involvement of initiation and progression of diverse kinds of human diseases, especially cancer. However, regulatory role, clinical significance and underlying mechanisms of circRNAs in triple-negative breast cancer (TNBC) still remain largely unknown.

Methods

Here, the expression profile of circRNAs in 4 pairs of TNBC tissues and adjacent non-tumor tissues was analyzed by RNA-sequencing. Quantitative real-time PCR and in situ hybridization were used to determine the level and prognostic values of circAGFG1 in two TNBC cohorts. Then, functional experiments in vitro and in vivo were performed to investigate the effects of circAGFG1 on tumor growth and metastasis in TNBC. Mechanistically, fluorescent in situ hybridization, dual luciferase reporter assay, RNA pull-down and RNA immunoprecipitation experiments were performed to confirm the interaction between circAGFG1 and miR-195-5p in TNBC.

Results

We found that circAGFG1 was evidently up-regulated in TNBC, and its level was correlated with clinical stage, pathological grade and poor prognosis of patients with TNBC. The results indicated that circAGFG1 could promote TNBC cell proliferation, mobility and invasion as well as tumorigenesis and metastasis in vivo. Mechanistic analysis showed that circAGFG1 may act as a ceRNA (competing endogenous RNA) of miR-195-5p to relieve the repressive effect of miR-195-5p on its target cyclin E1 (CCNE1).

Conclusions

Our findings suggest that circAGFG1 promotes TNBC progression through circAGFG1/miR-195-5p/CCNE1 axis and it may serve as a new diagnostic marker or target for treatment of TNBC patients.

Electronic supplementary material

The online version of this article (10.1186/s12943-018-0933-7) contains supplementary material, which is available to authorized users.

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Most cited references 27

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Targeting microRNAs in cancer: rationale, strategies and challenges.

Ramiro Garzon, Guido Marcucci, Carlo Croce (2010)

MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs that regulate gene expression. Early studies have shown that miRNA expression is deregulated in cancer and experimental data indicate that cancer phenotypes can be modified by targeting miRNA expression. Based on these observations, miRNA-based anticancer therapies are being developed, either alone or in combination with current targeted therapies, with the goal to improve disease response and increase cure rates. The advantage of using miRNA approaches is based on its ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. In this Review, we describe the role of miRNAs in tumorigenesis and critically discuss the rationale, the strategies and the challenges for the therapeutic targeting of miRNAs in cancer.

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Epigenetics and genetics. MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy.

Andrea L Kasinski, Frank J Slack (2011)

In normal cells multiple microRNAs (miRNAs) converge to maintain a proper balance of various processes, including proliferation, differentiation and cell death. miRNA dysregulation can have profound cellular consequences, especially because individual miRNAs can bind to and regulate multiple mRNAs. In cancer, the loss of tumour-suppressive miRNAs enhances the expression of target oncogenes, whereas increased expression of oncogenic miRNAs (known as oncomirs) can repress target tumour suppressor genes. This realization has resulted in a quest to understand the pathways that are regulated by these miRNAs using in vivo model systems, and to comprehend the feasibility of targeting oncogenic miRNAs and restoring tumour-suppressive miRNAs for cancer therapy. Here we discuss progress in using mouse models to understand the roles of miRNAs in cancer and the potential for manipulating miRNAs for cancer therapy as these molecules make their way towards clinical trials.

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The Circular RNA circPRKCI Promotes Tumor Growth in Lung Adenocarcinoma

Mantang Qiu, Wenjia Xia, Rui L. Chen … (2018)

Somatic copy number variations (CNV) may drive cancer progression through both coding and noncoding transcripts. However, noncoding transcripts resulting from CNV are largely unknown, especially for circular RNAs. By integrating bioinformatics analyses of alerted circRNAs and focal CNV in lung adenocarcinoma, we identify a proto-oncogenic circular RNA (circPRKCI) from the 3q26.2 amplicon, one of the most frequent genomic aberrations in multiple cancers. circPRKCI was overexpressed in lung adenocarcinoma tissues, in part due to amplification of the 3q26.2 locus, and promoted proliferation and tumorigenesis of lung adenocarcinoma. circPRKCI functioned as a sponge for both miR-545 and miR-589 and abrogated their suppression of the protumorigenic transcription factor E2F7 Intratumor injection of cholesterol-conjugated siRNA specifically targeting circPRKCI inhibited tumor growth in a patient-derived lung adenocarcinoma xenograft model. In summary, circPRKCI is crucial for tumorigenesis and may serve as a potential therapeutic target in patients with lung adenocarcinoma.Significance: These findings reveal high expression of the circular RNA circPRKCI drives lung adenocarcinoma tumorigenesis. Cancer Res; 78(11); 2839-51. ©2018 AACR.

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Author and article information

Contributors

Junxia Chen:

ORCID: http://orcid.org/0000-0002-8531-7562

chjunxia@126.com

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): 8 January 2019

Publication date PMC-release: 8 January 2019

Publication date Collection: 2019

Volume: 18

Electronic Location Identifier: 4

Affiliations

[1 ]ISNI 0000 0000 8653 0555, GRID grid.203458.8, Department of Cell Biology and Genetics, , Chongqing Medical University, ; #1 Yixueyuan Road, Chongqing, 400016 China

[2 ]GRID grid.452206.7, Department of Endocrine and breast surgery, , The First Affiliated Hospital of Chongqing Medical University, ; #1 Yixueyuan Road, Chongqing, 400016 China

Author information

Junxia Chen http://orcid.org/0000-0002-8531-7562

Article

Publisher ID: 933

DOI: 10.1186/s12943-018-0933-7

PMC ID: 6325825

PubMed ID: 30621700

SO-VID: 817251c5-7c38-40d0-bb32-0063b4fc7cf9

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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.

History

Date received : 28 September 2018

Date accepted : 27 December 2018

Funding

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

Award ID: 81672536

Award Recipient : Junxia Chen

Funded by: FundRef http://dx.doi.org/10.13039/501100007390, Instituto Nacional de Ciência e Tecnologia Centro de Estudos das Adaptações da Biota Aquática da Amazônia;

Award ID: BJRC201711

Award Recipient : Rui Yang

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: circagfg1,mir-195-5p,triple-nagetive breast cancer,ccne1

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: circagfg1, mir-195-5p, triple-nagetive breast cancer, ccne1

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The circRNA circAGFG1 acts as a sponge of miR-195-5p to promote triple-negative breast cancer progression through regulating CCNE1 expression

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

Related collections

Karger: Oncology

Most cited references 27

Targeting microRNAs in cancer: rationale, strategies and challenges.

Epigenetics and genetics. MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy.

The Circular RNA circPRKCI Promotes Tumor Growth in Lung Adenocarcinoma

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Cited by 181

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