Advances of circular RNAs in carcinoma

doi:10.1016/j.biopha.2018.07.164

Biomedicine & Pharmacotherapy

Volume 107, November 2018, Pages 59-71

https://doi.org/10.1016/j.biopha.2018.07.164 Get rights and content

Highlights

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Increasing studies have identified a correlation between circRNAs and different cancers.
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Most circRNAs are dysregulated in various cancers and some of them are critical in the development of tumors.
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This review summarized the biological functions of some circRNAs and recent advances in tumorigenesis and development.
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This review ultimately predicted the potential challenges of circRNAs in cancer research.

Abstract

Circular RNAs (circRNAs) are a type of non-coding RNAs with single-stranded closed structure. The rapid development of high-throughput sequencing technology has allowed for the widespread presence of circRNAs in transcriptomes. Moreover, increasing studies have identified a correlation between circRNAs and different cancers. In addition, most circRNAs are dysregulated in various cancers, and some of them have been reported be vital in the occurrence and development of tumors. For example, ciRS-7 plays a role in tumor promotion and circ-ITCH acts as a tumor suppressor. This review summarizes the latest progressions in the field regarding the functions of circRNAs in relation with cancers, and anticipates the emerging roles of circRNAs and future challenges in cancer research.

Introduction

Non-coding RNAs (ncRNAs), including circRNAs, long non-coding RNAs (lncRNAs), and short microRNAs (miRNAs) [1], account for 95% of total RNAs in eukaryotic transcription, which have obtained increasing appreciation and has played important roles in gene regulation [2,3]. Many studies have been done on lncRNAs and miRNAs, but few on circRNAs [4]. Moreover, circRNAs were considered errors and non-functional in normal splicing processes since their discovery in viruses nearly 40 years ago [[5], [6], [7]]. With the rapid developments in high-throughput sequencing, the widespread and large presence of circRNAs in transcriptomes have recently been demonstrated [8]. Currently, circRNAs are considered to be influential modulators in cellular differentiation and tissue homeostasis, as well as in disease development [1,7].

The 2015 statistics from the National Cancer Center in China showed 4,292,000 new cancer cases and 2,814,000 deaths due to carcinomas [9]. In China, lung cancer has the highest morbidity and mortality due to tumors; moreover, lung cancer, gastric cancer, liver cancer, esophageal cancer, and colorectal cancer are the five most common cancers and have been identified as the leading causes of cancer deaths [10]. Therefore, early diagnosis of carcinoma and effective treatment are vital. In recent years, researchers have tried to explore whether circRNAs could act as potential biomarkers for early diagnosis and therapeutic targets. This review will provide an overview of the features, biological functions and research advancements of circRNAs in different tumors.

Section snippets

The characteristics of circRNAs

CircRNAs, a type of non-coding RNA consisting of at least a few hundred nucleotides, are widely present in eukaryotes. Moreover, circRNAs are single-stranded closed RNA molecules that undergo canonical or non-canonical splicing [11,12]. CircRNAs are characterized by covalently closed-loop structures with neither 5ʹ to 3ʹ ends nor a poly-adenylated tail; moreover, circRNAs are not easily degraded by endonucleases [7,13]. Due to their closed-loop structure and lack of effective

Functions of circRNAs

According to various origins, circRNAs can be divided into three types, namely, exonic circRNAs (ecircRNAs), intronic circRNAs (ciRNAs), and exon-intron circRNAs (EIciRNAs) [[21], [22], [23], [24]]. Over 80% of the circRNAs formed by exons are stably distributed in the cytoplasm, whereas ciRNAs and EIciRNAs are mainly distributed in the nucleus [23,25]. Currently, other than the few circRNAs that can be translated into proteins, such as circ-ZNF609 [26] and circ-SHPRH [27], most circRNAs act as

Research of circRNAs in solid tumors

Emerging evidence has showed that circRNAs are closely associated with clinical characteristics of human cancers, such as tumorigenesis [41,42], development [43,44], invasion [45], metastasis [46], and chemo-radiation resistance [47], as well as the prognosis of cancers [48]. However, studies on the roles of circRNAs in various cancers are still in their infancy. In our review, we summarized the biological functions and mechanisms of circRNAs in promoting or suppressing tumorigenesis and in

Circ-ITCH

Circ-ITCH is a circular RNA derived from several exons of itchy E3 ubiquitin protein ligase (ITCH) and is located on chromosome 20q11.22 on the plus strand [49,50]. The ITCH protein can promote the degradation of phosphorylated Dishevelled-2 (Dvl2), which is an important regulator for Wnt/β-catenin signaling activation. CCND1 is a classic oncogene that promotes G1-S progression by sequentially phosphorylating retinoblastoma proteins in human cancers [51]. c-Myc and the cell cycle regulator

CiRS-7

MicroRNA-7 (miR-7) is one of the endogenous noncoding RNA molecules that contains 23 nucleotides and located in chromosome 15 [84]; moreover, miR-7 is an important suppressor in breast cancer [85,86], NSCLC [87], pancreatic cancer [88], and gastric cancer [89]. CiRS-7, also known as the natural antisense transcript of cerebellar degeneration-associated protein 1 (CDR1), harbors more than 70 conventional binding sites and functions as a super sponge for miR-7 [3]; ciRS-7 is upregulated in GC [89

Early diagnosis of tumors

Early diagnosis is vital in improving cancer prognosis. Current tumor biomarkers for screening tumors include embryonal antigens, such as carcinoembryonic antigen (CEA) or α-fetoprotein (AFP), carbohydrate antigen (CA199, CA153, and CA125), and tumor-related enzymes (prostate cancer antigen (PSA) or neuron-specific enolase (NSE)). However, the accuracy and specificity of these biomarkers still need to be improved.

HCC is the third leading cause of cancer-related deaths in China [9]. Most HCC

CircRNAs and chemo-radiation resistance

CircRNA_0006528 is negatively correlated with miR-7-5p expression and miR-7-5p was downregulated in Adriamycin (ADM)-resistant breast cancer tissues and cells. Raf1 mRNA and protein levels are downregulated following the knockdown of circRNA_0006528. Moreover, Raf1 mRNA and protein levels are up-regulated when miR-7-5p is over-expressed in ADM-resistant breast cancer cell lines [47]. As a result, the circRNA_0006528-miR-7-5p-Raf1 axis may be responsible for ADM resistance in breast cancer.

Conclusions and prospects

CircRNAs, a class of non-coding RNAs, play important roles in the occurrence and development of many diseases, especially tumors. A majority of studies on circRNAs delve into tumorigenesis, proliferation, metastasis, and invasion of tumors. We suppose that circRNAs have great potential for diagnosing and treating tumors. However, the research of circRNAs is still in infancy and multiplex problems are still waiting to be solved such as the lack of a common standard for naming circRNAs.

Conflicts of interest

None.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No 81402483 and 81503528), and the talents program of Jiangsu Cancer Hospital.

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Therefore, circRNAs may play an important role in the regulation of gene transcription in different organisms. Initially, because of their closed-loop structure and lack of effective intracellular ribosome insertion sites, circRNAs were considered to lack translation function [39]. However, circRNAs were found to bind to ribosomes in 1995, implying that they could act as mRNAs to direct protein synthesis [40].
Circular RNAs (circRNAs) are RNA molecules with a stable closed-loop structure that are found in a variety of organisms. CircRNAs are highly stable and conserved, and they play important roles in transcriptional regulation and splicing. Multiple Myeloma (MM) is a malignant proliferative disease for which there are currently no effective and comprehensive treatments. Numerous circRNAs may contribute to the development and progression of MM by acting as oncogenes or regulators. Due to the unique function of circRNAs, they have a high potential for regulating the biological functions (including proliferation and apoptosis) of MM cells, and their expression levels and molecular mechanism are closely related to their diagnostic value, therapeutic sensitivity, and clinical prognosis of MM patients. In this review, we aim to provide a detailed overview of the structure and function of circRNAs and demonstrate the potential therapeutic value and potential mechanism of circRNAs in MM via experiments and clinical trials.
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Current explorations also emphasize the promising effects of circRNAs in the diagnosis and prognosis of ocular diseases (Han et al., 2017; Shan et al., 2017; Gu et al., 2017). Under diabetic conditions, dysregulation of circDNMT3B/miR-20b-5p axis (Zhu et al., 2019), circHIPK3/miR-30a-3p axis (Shan et al., 2017), cZNF609 (Liu et al., 2017) were both confirmed to contribute to DR, indicating the importance of circRNAs in DR. Circ-ITCH, originates from itchy E3 ubiquitin protein ligase, is located on chromosome 20q11.22 (Xu et al., 2018). Researchers have verified that the ectopic expression of circ-ITCH was closely related to overall prognosis of numerous carcinomas (Xu et al., 2018; Hansen et al., 2013; Ren et al., 2019; Yang et al., 2018).
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¹: These authors contributed equally to this work.

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ReviewAdvances of circular RNAs in carcinoma

Highlights

Abstract

Introduction

Section snippets

The characteristics of circRNAs

Functions of circRNAs

Research of circRNAs in solid tumors

Circ-ITCH

CiRS-7

Early diagnosis of tumors

CircRNAs and chemo-radiation resistance

Conclusions and prospects

Conflicts of interest

Acknowledgements

Mol. Cell

Clin. Chim. Acta

Biochim. Biophys. Acta

Mol. Cell

Mol. Cell

J. Mol. Biol.

Cell

Cell

Mol. Cell

Cancer Lett.

Mol. Cancer

Cancer Cell

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Diagn. Pathol.

Cell

Hepatobiliary Pancreat. Dis. Int.

Cancer Lett.

Toxicol. Lett.

J. Biol. Chem.

J. Hepatol.

Circular RNAs as potential biomarkers for cancer diagnosis and therapy

Am. J. Cancer Res.

Circular RNA and miR-7 in cancer

Cancer Res.

Natural RNA circles function as efficient microRNA sponges

Nature

Molecular biology: circles reshape the RNA world

Nature

Molecular biology. A circuitous route to noncoding RNA

Science

Mis-splicing yields circular RNA molecules

FASEB J.

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

Nature

Circular RNAs are abundant, conserved, and associated with ALU repeats

Rna

Cancer statistics in China, 2015

CA Cancer J. Clin.

Global cancer statistics, 2012

CA Cancer J. Clin.

Efficient backsplicing produces translatable circular mRNAs

Rna

Internal ribosome entry sites tests with circular mRNAs

Methods Mol. Biol.

Circular RNAs: isolation, characterization and their potential role in diseases

RNA Biol.

Detecting and characterizing circular RNAs

Nat. Biotechnol.

Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis

Cell Res.

CircRNA: functions and properties of a novel potential biomarker for cancer

Mol. Cancer

Electron microscopic evidence for the circular form of RNA in the cytoplasm of eukaryotic cells

Nature

Expanded identification and characterization of mammalian circular RNAs

Genome Biol.

Exon-intron circular RNAs regulate transcription in the nucleus

Nat. Struct. Mol. Biol.

Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis

Mol. Cell

A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis

Oncogene

Circular RNAs in cancer: novel insights into origins, properties, functions and implications

Am. J. Cancer Res.

Review
Advances of circular RNAs in carcinoma