Dysregulation Of circRNAs Research Articles

Circular RNAs as important players in human gastric cancer.

As one of the most prevalent gastrointestinal diseases, gastric cancer (GC) is the second leading cause of cancer-related deaths worldwide. Since GC has no clinical manifestations in the early stage of the disease, most patients are detected in the later phases of disease and have an unfortunately lower chance of recovery. Circular RNAs (circRNAs), a novel category of non-coding RNAs (ncRNAs), are mainly engaged in the regulation of gene expression at the transcriptional and post-transcriptional levels. Numerous evidences have revealed that circRNAs play key roles in GC as they are involved in cell proliferation, growth, and apoptosis via modulating the expression of some target genes, miRNAs, and proteins. Many studies have addressed the impact of circRNA dysregulation on GC initiation, progression, and invasion via binding to miRNAs or RNA binding proteins. Moreover, changes in circRNA expression are associated with pathological and clinical features of GC highlighting their potentials as diagnostic or prognostic biomarkers in GC. In the current study, the recent findings on the significance of circRNAs in the development and progression of GC are reviewed. We focus on the implications of circRNAs as potential diagnostic or prognostic biomarkers in this malignancy.

The Emerging Role and Promise of Circular RNAs in Obesity and Related Metabolic Disorders.

Circular RNAs (circRNAs) are genome transcripts that are produced from back-splicing of specific regions of pre-mRNA. These single-stranded RNA molecules are widely expressed across diverse phyla and many of them are stable and evolutionary conserved between species. Growing evidence suggests that many circRNAs function as master regulators of gene expression by influencing both transcription and translation processes. Mechanistically, circRNAs are predicted to act as endogenous microRNA (miRNA) sponges, interact with functional RNA-binding proteins (RBPs), and associate with elements of the transcriptional machinery in the nucleus. Evidence is mounting that dysregulation of circRNAs is closely related to the occurrence of a range of diseases including cancer and metabolic diseases. Indeed, there are several reports implicating circRNAs in cardiovascular diseases (CVD), diabetes, hypertension, and atherosclerosis. However, there is very little research addressing the potential role of these RNA transcripts in the occurrence and development of obesity. Emerging data from in vitro and in vivo studies suggest that circRNAs are novel players in adipogenesis, white adipose browning, obesity, obesity-induced inflammation, and insulin resistance. This study explores the current state of knowledge on circRNAs regulating molecular processes associated with adipogenesis and obesity, highlights some of the challenges encountered while studying circRNAs and suggests some perspectives for future research directions in this exciting field of study.

Circular RNA HIPK3: A Key Circular RNA in a Variety of Human Cancers.

Circular RNAs (circRNAs), which act as initiators and promoters of various diseases, were thought to be mostly noncoding RNAs (ncRNAs) in eukaryotes, until recent studies confirmed that some circRNAs have the function of encoding proteins. Accumulating research findings have proved that dysregulation of circRNAs is associated with the developmental process of multiple cancers. circHIPK3, an example of circRNA, is frequently expressed in many diseases, such as diabetes, age-related cataract, idiopathic pulmonary fibrosis, preeclampsia, osteoblasts, and retinal vascular dysfunction, leading to disease development and progression. In addition, circHIPK3 may also serve as a potential biomarker, to help us know more about the rules of occurrence and development of cancers. In recent studies, many circHIPK3-related cancers have been identified, including nasopharyngeal carcinoma, gallbladder cancer, lung cancer, hepatocellular carcinoma, osteosarcoma, glioma, colorectal cancer, ovarian cancer, bladder cancer, prostate cancer, gastric cancer, oral squamous cell carcinoma, and chronic myeloid leukemia. This review summarizes recent studies on the biological mechanisms of circHIPK3 and expounds the molecular mechanisms of circHIPK3 in these malignant tumors.

Circular RNA circCCDC9 acts as a miR-6792-3p sponge to suppress the progression of gastric cancer through regulating CAV1 expression

BackgroundAs a novel type of noncoding RNAs, covalently closed circular RNAs (circRNAs) are ubiquitously expressed in eukaryotes. Emerging studies have related dysregulation of circRNAs to tumorigenesis. However, the biogenesis, regulation, function and mechanism of circRNAs in gastric cancer (GC) remain largely unclear.MethodsThe expression profile of circRNAs in 6 pairs of GC tissues and adjacent non-tumor tissues was analyzed by RNA-sequencing. Quantitative real-time PCR was used to determine the expression level of circCCDC9 in GC tissues and cell lines. Then, functional experiments in vitro and in vivo were employed to explore the effects of circCCDC9 on tumor growth and metastasis in GC. Mechanistically, dual luciferase reporter, fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down assays were performed to confirm that circCCDC9 directly sponged miR-6792-3p and alleviated suppression on target CAV1 expression.ResultsEvidently down-regulated expression of circCCDC9 was observed in both GC tissues and cell lines. Expression of circCCDC9 was negatively correlated with tumor size, lymph node invasion, advanced clinical stage and overall survival in GC patients. Functionally, overexpression of circCCDC9 significantly inhibited the proliferation, migration and invasion of GC cell lines in vitro and tumor growth and metastasis in vivo, whereas miR-6792-3p mimics counteracted these effects. Mechanistic analysis demonstrated that circCCDC9 acted as a “ceRNA” of miR-6792-3p to relieve the repressive effect of miR-6792-3p on its target CAV1, then suppressed the tumorigenesis of GC.ConclusionsCircCCDC9 functions as a tumor suppressor in inhibiting the progression of GC through miR-6792-3p/CAV1 axis, which has provided an exploitable biomarker and therapeutic target for patients with GC.

Dysregulation of CircRNA_0001946 Contributes to the Proliferation and Metastasis of Colorectal Cancer Cells by Targeting MicroRNA-135a-5p.

This study was aimed to evaluate the potential function of circ-0001946 in the progression of colorectal cancer (CRC) and the related regulatory mechanism. First, the expression levels of circRNA_0001946 and microRNA-135a-5p (miR-135a-5p) in normal and CRC tissues were measured by quantitative real-time polymerase chain reaction (RT-qPCR). In addition, cell proliferation was assessed by the Cell Counting Kit-8 (CCK-8) assay, cell migration and invasion were evaluated by Transwell assays, and the cell cycle patterns were determined by flow cytometry. The relationship between the expression levels of circ_0001946 and miR-135a-5p was determined by dual-luciferase reporter assays. Our data showed that the expression of circ_0001946 was upregulated in CRC tissues, which was negatively correlated with tumor size, histologic grade, lymphatic metastasis, and TMN stage, and patients with circ_0001946 overexpression were more likely to have a poor prognosis. In addition, in vitro experiments showed that silencing circ_0001946 inhibited the epithelial–mesenchymal transition (EMT) pathway and markedly suppressed CRC cell growth, migration, and invasion. Furthermore, we discovered that the transfection of miR-135a-5p mimics could reverse the antitumor effects of circRNA_0001946 downregulation. To summarize, this study revealed that circRNA_0001946 might act as a tumor promoter by activating the miR-135a-5p/EMT axis and may be a promising treatment target for CRC.

Circular RNAs: new genetic tools in melanoma.

Melanoma is the most lethal form of skin cancer. New technologies have resulted in major advances in the diagnosis and treatment of melanoma and other cancer types. Recently, some studies have investigated the role of circular RNAs (circRNAs) in different cancers. CircRNAs are a member of long noncoding RNA family mainly formed through back-splicing and have a closed-loop structure. These molecules affect several biological and oncogenic cascades in diverse ways via acting as microRNA sponge, interacting with RNA-binding proteins and acting as a transcription regulator. In this review, we made an insight into the impact of circRNA dysregulation in the melanoma tumorigenesis based on the presented evidences.

Profiling and bioinformatics analyses reveal chronic lymphocytic leukemia cells share a unique circular RNA expression pattern

Approximately 10% of the human transcriptome is composed of circular RNAs (circRNAs). These are non-coding RNA molecules in which a covalent bond between the 3' and 5' forms a stable circular loop. Herein, we profiled the expression of 13,368 cricRNAS in 21 patients with chronic lymphocytic leukemia (CLL). Regardless of clinical, genetic, or prognostic characteristics, CLL cells share a unique expression profile distinguishable from that of normal B cells. Specifically, 859 circRNAs from 592 genes were differentially expressed (fold change ≥2 and false discovery rate ≤0.05). Whether dysregulation of circRNAs contributes to the pathogenesis of CLL remains to be determined.

Genome-wide, integrative analysis of circular RNA dysregulation and the corresponding circular RNA-microRNA-mRNA regulatory axes in autism.

Circular RNAs (circRNAs), a class of long noncoding RNAs, are known to be enriched in mammalian neural tissues. Although a wide range of dysregulation of gene expression in autism spectrum disorder (ASD) have been reported, the role of circRNAs in ASD remains largely unknown. Here, we performed genome-wide circRNA expression profiling in postmortem brains from individuals with ASD and controls and identified 60 circRNAs and three coregulated modules that were perturbed in ASD. By integrating circRNA, microRNA, and mRNA dysregulation data derived from the same cortex samples, we identified 8170 ASD-associated circRNA-microRNA-mRNA interactions. Putative targets of the axes were enriched for ASD risk genes and genes encoding inhibitory postsynaptic density (PSD) proteins, but not for genes implicated in monogenetic forms of other brain disorders or genes encoding excitatory PSD proteins. This reflects the previous observation that ASD-derived organoids show overproduction of inhibitory neurons. We further confirmed that some ASD risk genes (NLGN1, STAG1, HSD11B1, VIP, and UBA6) were regulated by an up-regulated circRNA (circARID1A) via sponging a down-regulated microRNA (miR-204-3p) in human neuronal cells. Particularly, alteration of NLGN1 expression is known to affect the dynamic processes of memory consolidation and strengthening. To the best of our knowledge, this is the first systems-level view of circRNA regulatory networks in ASD cortex samples. We provided a rich set of ASD-associated circRNA candidates and the corresponding circRNA-microRNA-mRNA axes, particularly those involving ASD risk genes. Our findings thus support a role for circRNA dysregulation and the corresponding circRNA-microRNA-mRNA axes in ASD pathophysiology.

Downregulation of circular RNA circPVT1 restricts cell growth of hepatocellular carcinoma through downregulation of Sirtuin 7 via microRNA-3666.

Circular RNAs (circRNAs) have been identified recently as pivotal regulators in the development and progression of cancers, generally by acting as competing endogenous RNAs of microRNAs (miRNAs) to regulate gene expression. The dysregulation of circRNAs in hepatocellular carcinoma (HCC) has attracted much attention, but the precise role of circRNAs in HCC remains largely unknown. In this study, we aimed to investigate the potential role of circular RNA PVT1 (circPVT1), a newly identified cancer-related circRNA, in HCC. Herein, we found that circPVT1 expression was significantly upregulated in HCC tissues and cell lines. Knockdown of circPVT1 significantly reduced the growth and colony formation, and increased cell apoptosis, of HCC cells. Our results further identified circPVT1 as a sponge for miR-3666. Knockdown of circPVT1 significantly increased miR-3666 expression in HCC cells. Moreover, miR-3666 expression was significantly downregulated in HCC tissues and was inversely correlated with circPVT1 expression. In addition, the overexpression of miR-3666 inhibited the growth of HCC cells by targeting Sirtuin 7 (SIRT7). Notably, miR-3666 inhibition or SIRT7 overexpression partially reversed the circPVT1 knockdown-mediated inhibitory effect on HCC cell growth. Overall, these results demonstrate that downregulation of circPVT1 represses HCC cell growth by upregulating miR-3666 to inhibit SIRT7, suggesting circPVT1 as a potential therapeutic target for HCC. Our study highlights the involvement of circPVT1/miR-3666/SIRT7 in regulating HCC cell growth.

Screening Circular RNAs Related to Acquired Gefitinib Resistance in Non-small Cell Lung Cancer Cell Lines

Background: Gefitinib is a tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) used to treat EGFR mutation-positive patients with non-small cell lung cancer (NSCLC). However, the efficacy of gefitinib is limited by the development of acquired resistance. Studies have shown that circular RNAs (circRNAs) are involved in the acquired resistance to many anticancer agents. However, the expression profiles and functions of circRNAs in gefitinib resistance in NSCLC are poorly understood so far.Methods: In this study, circRNA expression profiling was explored in two gefitinib-resistant NSCLC cell lines (HCC827/GR and PC9/GR) and their parental sensitive cells (HCC827 and PC9) using high-throughput RNA sequencing. Quantitative real-time PCR (qRT-PCR) was used to confirm the expression of selected differentially expressed circRNAs. Bioinformatic tools including gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), network analysis, and Kaplan-Meier plotter database were used to predict the functions and pathways of these differentially expressed circRNAs.Results: We identified 46 and 56 differentially expressed circRNAs in HCC827/GR and PC9/GR cell lines, respectively, compared with those in their parental cell lines. Gene ontology and KEGG pathway analysis identified that the host linear transcripts of these differentially expressed circRNAs were involved in many critical biological pathways and molecular functions. We found that hsa_circ_0000567 was consistently up-regulated, and hsa_circ_0006867 was consistently down-regulated in two resistant cell lines. We further used hsa_circ_0000567 and hsa_circ_0006867 as key circRNAs to construct circRNA-miRNA-mRNA networks. Several target mRNAs of these two circRNAs had been shown to significantly associate with the overall survival of patients with lung cancer.Conclusions: In this study, we generated the comprehensive expression and functional profiles of the differentially expressed circRNAs between gefitinib-resistant and -sensitive NSCLC cells, and showed that dysregulation of circRNAs might play an important role in the development of acquired resistance to gefitinib in NSCLC.

Circular RNA MTO1 Inhibits the Proliferation and Invasion of Ovarian Cancer Cells Through the miR-182-5p/KLF15 Axis

Circular RNAs (circRNAs) are a novel class of endogenous noncoding RNAs and have been shown to play important roles in a variety of physiological processes. Recently, dysregulation of circRNAs has been identified in many types of cancers. In this study, we analyzed the expression profile and biological functions of circMTO1 in ovarian cancer. We demonstrated that circMTO1 was downregulated in ovarian cancer tissues and cell lines. Upregulation of circMTO1 inhibited proliferation and invasion of ovarian cancer cells while downregulation of circMTO1 promoted these processes. Mechanistically, we showed that circMTO1 sponged miR-182-5p to support KLF15 expression, eventually leading to inhibition of ovarian cancer progression. In conclusion, our study suggested circMTO1 as a novel biomarker and therapeutic target for ovarian cancer treatment.

Circular RNAs and gastrointestinal cancers: Epigenetic regulators with a prognostic and therapeutic role.

Both environmental and genetic factors are involved in the initiation and development of gastrointestinal cancer. Covalent closed circular RNAs (circRNAs) are produced by a mechanism called "back-splicing" from mRNAs. They are highly stable and show cell and tissue specific expression patterns. Although some functions such as "microRNA sponge" and "RNA binding protein sponge" have been reported for a small number of circRNAs, the function of thousands of other circRNAs is still unknown. Dysregulation of circRNAs has been reported in many GI cancers and are involved in metastasis and invasion. CircRNAs have been reported to be useful as prognostic markers and targets for developing new treatments. We first describe the properties and biogenesis of circRNAs. We then summarize recent reports about circRNA functions, expression status, and their potential to be used as biomarkers in GI cancers including, gastric cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, gallbladder cancer and pancreatic cancer.

Increased circulating circular RNA_103516 is a novel biomarker for inflammatory bowel disease in adult patients.

BACKGROUNDIncreasing evidence demonstrates that by acting as microRNA sponges modulating gene expression at the transcriptional or post-transcriptional level, circular RNAs (circRNAs) participate in the pathogenesis of a variety of diseases and are considered ideal biomarkers of human disease.AIMTo examine the expression of circRNA_103516 in inflammatory bowel disease (IBD) and its associations with clinical phenotypes and inflammatory cytokines.METHODSPeripheral blood mononuclear cells (PBMCs) were obtained from patients with IBD, healthy controls (HCs), and patient controls (PCs). Expression of circRNA_103516 and hsa-miR-19b-1-5p was assessed by quantitative reverse transcription-polymerase chain reaction. Crohn's disease activity index (CDAI), Mayo score, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR) were measured. To assess the inflammatory cytokines tumour necrosis factor α (TNF-α), interferon-γ (IFN-γ), and interleukin-10 (IL-10), blood samples were analysed by flow cytometry.RESULTSNinety Crohn’s disease (CD) and 90 ulcerative colitis (UC) patients, 80 HCs, and 35 PCs were included in the study. CircRNA_103516 was upregulated in CD and UC patients compared with HCs and PCs (P < 0.05). The area under the curve of circRNA_103516 for diagnosing CD and UC was 0.790 and 0.687, respectively. In addition, circRNA_103516 levels were increased in active CD and UC compared with remittent groups (P = 0.027, P = 0.045). Furthermore, in CD, circRNA_103516 correlated positively with CDAI (P < 0.001), CRP (P < 0.001), ESR (P < 0.001), TNF­α (P < 0.001), and IFN-γ (P < 0.001) and negatively correlated with IL-10 (P = 0.006). In UC patients, circRNA_103516 correlated with Mayo score (P < 0.001), CRP (P < 0.001), ESR (P < 0.001), TNF­α (P < 0.001), IFN-γ (P =0.011), and IL-10 (P = 0.002). Additionally, circRNA_103516 correlated positively with stricturing (P = 0.018) and penetrating (P = 0.031) behaviour. Moreover, hsa-miR-19b-1-5p correlated negatively with circRNA_103516 in CD.CONCLUSIONCircRNA_103516 levels in PBMCs can be considered an ideal candidate biomarker for diagnosing IBD. Dysregulation of circRNA_103516 may participate in the molecular mechanism of IBD through hsa-miR-19b-1-5p sponging.

Identification of Circular RNAs Regulating Islet β-Cell Autophagy in Type 2 Diabetes Mellitus.

This study is to identify the circular RNA (circRNA) expression profile that is functionally related to pancreatic islet β-cell autophagy and their potential regulation mechanisms in type 2 diabetes mellitus (T2DM). T2DM rat model was constructed by administration of high-fat and high-sugar diet. β-cells were isolated from islets by flow cytometry. CircRNA expression profile in β-cells was detected by circRNA microarrays, and the differentially expressed circRNAs were identified and validated by qRT-PCR. MicroRNA (miRNA) target prediction software and multiple bioinformatic approaches were used to construct a map of circRNA-miRNA interactions for the differentially expressed circRNAs. A total of 825 differentially expressed circular transcripts were identified in T2DM rats compared with control rats, among which 388 were upregulated and 437 were downregulated. Ten circRNAs were identified to have significant differences by qRT-PCR. GO analysis enriched terms such as organelle membrane and protein binding and the top enriched pathways for the circRNAs included MAPK signaling pathway. The differentially expressed circRNAs might involve in MAPK signaling pathway, apoptosis, and Ras signaling pathway. We speculate that these circRNAs, especially rno_circRNA_008565, can regulate the autophagy of islet β-cells via interactions with miRNA. Dysregulation of several circRNAs may play a role in T2DM development, and rno_circRNA_008565 may be a potential regulator of β-cell autophagy.

Effects of circular RNA circ-SOD2 on intestinal epithelial barrier and ulcerative colitis

OBJECTIVE To explore the expression profiling of circRNAs in ulcerative colitis(UC) and then determine the significantly changed circRNA and its influences on intestinal epithelial barrier. METHODS In this study, we selected 5 pairs of inflamed and normal colorectal mucosa tissues from UC patients to perform circRNAs microarray and identified the differentially expressed circRNAs in the UC inflamed colorectal mucosa tissues, and quantitative real-time PCR was used to identify the expression change of circ-SOD2 in 30 UC patients' inflamed and normal colorectal mucosa tissues. We detected the expression of circ-SOD2 in Caco2 and NCM460 cells after being treated with inflammatory factors (LPS, TNF-α, IL1-β). Fluorescence in situ hybridization (FISH) was used to determine the cellular location of circ-SOD2 in the UC colorectal mucosal tissues. The circ-SOD2 overexpression vector was constructed and produced and then transfected into Caco2 cells to examine the cells' trans-epithelial electrical resistance (TEER), permeability of FITC-dextran and the alterations of epithelial barrier related molecules. RESULTS We found 264 circRNAs (111 increased and 153 decreased) differentially expressed in the inflamed colon mucosa compared with normal colon mucosa using a P-value 1.5-fold change cutoff. To validate the circRNA microarray results, we selected some circRNAs to perform qRT-PCR based on the following criteria: (1) circRNAs raw data >100 in each sample, (2) fold-change >2, (3) P<0.05. We identified 10 dysregulated circRNA, among them, circ-SOD2 was upregulated with maximum fold-change in the UC inflamed colorectal mucosa tissues. Then we identified circ-SOD2 was upregulated significantly through quantitative real-time PCR (qRT-PCR) in expanded 30 paired colorectal mucosa tissues(P<0.001). After treatments with LPS, TNF-α and IL1-β, circ-SOD2 was upregulated in Caco2 and NCM460 cells at different points from 1 to 7 h. Fluorescence in situ hybridization (FISH) indicated that circ-SOD2 located in intestinal epithelium mostly and few in mesenchyme and inflammatory cells. The overexpression of circ-SOD2 in Caco2 cells resulted in a decrease of transepithelial electrical resistance (TEER), an increase of the FITC-dextran permeability and the downregulation of epithelial barrier related molecule CLDN-8 (P<0.05). CONCLUSION The dysregulation of circRNAs existed in UC inflamed colorectal mucosa, among which, the upregulated circ-SOD2 weakened the intestinal epithelial barrier and thus might promote the occurrence of ulcerative colitis.

Circular RNAs: pivotal molecular regulators and novel diagnostic and prognostic biomarkers in non-small cell lung cancer.

Circular RNAs (circRNAs), a large class of non-coding RNAs with covalently closed-loop structures, are abundant, stable, conserved, and have tissue and developmental-stage specificities. The biological functions of circRNAs are varied. Moreover, circRNAs participate in various pathological processes, especially in multiple cancers. Lung cancer is the most frequent malignant tumor worldwide. Many studies have suggested that circRNAs are pivotal in non-small cell lung cancer. This article aims to provide a retrospective review of the latest research on the functions of circRNAs in non-small cell lung cancer. In particular, we focus our discussion on the role of circRNAs in cell-cycle regulation and the epithelial-mesenchymal transition, and also discuss the known regulatory molecular mechanisms of circRNAs in non-small cell lung cancer. We reviewed the literature on circRNAs and non-small cell lung cancer from PubMed databases. Specifically, we focused on the roles and mechanisms of circRNAs in regulating the cell cycle and the epithelial-mesenchymal transition. Dysregulation of circRNAs is closely correlated with proliferation, migration, and invasion of non-small cell lung cancer, especially in terms of modulating cell-cycle regulation and the epithelial-mesenchymal transition. Taken together, circRNAs have potential as biomarkers for the diagnosis, prognosis, and treatment of non-small cell lung cancer.

Possible epigenetic regulatory effect of dysregulated circular RNAs in Alzheimer\u2019s disease model

As circular RNAs (circRNAs) regulates the effect of micro RNAs (miRNAs), circRNA–miRNA-mRNA network might be implicated in various disease pathogenesis. Therefore, we evaluated the dysregulated circRNAs in the Tg2576 mouse Alzheimer’s disease (AD) model, their possible regulatory effects on downstream target mRNAs, and their pathomechanistic role during the disease progression. The microarray-based circRNA expression analysis at seven- and twelve-months of ages (7 M and 12 M) returned 101 dysregulated circRNAs at 7 M (55 up-regulated and 46 down-regulated) and twelve dysregulated circRNAs at 12 M (five up-regulated and seven down-regulated). For each dysregulated circRNA, potential target miRNAs and their downstream target mRNAs were searched. Dysregulation of circRNAs was associated with increased frequency of relevant dysregulation of their downstream target mRNAs. Those differentially expressed circRNA–miRNA-mRNA regulatory network included 2,275 networks (876 for up-regulated circRNAs and 1,399 for down-regulated circRNAs) at 7 M and 38 networks (25 for up-regulated circRNAs and 13 for down-regulated circRNAs) at 12 M. Gene ontology (GO) and pathway analyses demonstrated that the dysregulated mRNAs in those networks represent the AD pathomechanism at each disease stage. We concluded that the dysregulated circRNAs might involve in the AD pathogenesis by modulating disease relevant mRNAs via circRNA–miRNA-mRNA regulatory networks.

Identification of circular RNAs hsa_circ_0044235 and hsa_circ_0068367 as novel biomarkers for systemic lupus erythematosus

Circular RNAs (circRNAs) have emerged as novel biomarkers for disease diagnosis. However, the expression profiles and clinical significance of circRNAs in peripheral blood mononuclear cells (PBMCs) from systemic lupus erythematosus (SLE) remain unclear. In the present study, the expression profile of circRNAs in PBMCs from patients with SLE and healthy controls (HCs) was detected by using microarray analysis and verified by reverse transcription-quantitative polymerase chain reaction. A total of 1,603 circRNAs were identified to be significantly aberrantly expressed in PBMCs from patients with SLE. Validation assays in 30 SLE patients and 20 HCs demonstrated that the levels of hsa_circ_0044235 and hsa_circ_0068367 were significantly decreased in the patients with SLE. Receiver operating characteristic curve analysis suggested that hsa_circ_0044235 and hsa_circ_0068367 were significant for SLE diagnosis. Furthermore, the diagnostic potential of hsa_circ_0044235 and hsa_circ_0068367 for SLE was validated in an independent validation set with 45 patients with SLE, 38 HCs and 30 patients with rheumatoid arthritis. In addition, the level of hsa_circ_0044235 in the PBMCs from patients with SLE were identified to be significantly increased in new-onset SLE patients and in patients who were determined to be positive for anti-double-stranded DNA and anti-ribosomal protein P antibodies. Additionally, the level of a microRNA (miRNA) target of hsa_circ_0044235, hsa-miRNA-892a, was identified to be significantly increased in the PBMCs from patients with SLE. The present study suggested that the dysregulation of circRNAs may serve a role in SLE pathogenesis, and that the levels of hsa_circ_0044235 and hsa_circ_0068367 in PBMC have potential as biomarkers for SLE diagnosis.

The RNA-binding protein RBM3 promotes cell proliferation in hepatocellular carcinoma by regulating circular RNA SCD-circRNA 2 production

BackgroundWith the development of RNA-seq technology, tens of thousands of circular RNAs (circRNAs), a novel class of RNAs, have been identified. However, little is known about circRNA formation and biogenesis in hepatocellular carcinoma (HCC).MethodsWe performed ribosomal-depleted RNA-seq profiling of HCC and para-carcinoma tissues and analyzed the expression of a hotspot circRNA derived from the 3’UTR of the stearoyl-CoA desaturase (SCD) gene, termed SCD-circRNA 2.FindingsIt was significantly upregulated in HCC and correlated with poor patient prognosis. Moreover, we observed that the production of SCD-circRNA 2 was dynamically regulated by RNA-binding protein 3 (RBM3). RBM3 overexpression was indicative of a short recurrence-free survival and poor overall survival for HCC patients. Furthermore, by modulating the RBM3 or SCD-circRNA 2 levels, we found that RBM3 promoted the HCC cell proliferation in a SCD-circRNA 2 dependent manner.InterpretationHerein, we report that RBM3 is crucial for the SCD-circRNA 2 formation in HCC cells, which not only provides mechanistic insights into cancer-related circRNA dysregulation but also establishes RBM3 as an oncogene with both therapeutic potential and prognostic value.FundThis work was supported by the National Key Research and Development Program of China (2016YFC1302303), the National Natural Science Foundation of China (Grant No. 81672345 and 81,402,269). The funders did not have any roles in study design, data collection, data analysis, interpretation, writing of the report.

Dysregulated circRNA_100876 suppresses proliferation of osteosarcoma cancer cells by targeting microRNA-136.

The aim of this study was to explore the regulatory mechanism of circRNA_100876/ microRNA-136 (miR-136) axis in the development and progression of osteosarcoma cancer. Quantitative real-time polymerase chain reaction (RT-qPCR) was used to evaluate the expression levels of circRNA_100876 and miR-136 in osteosarcoma cancer samples and the adjacent nontumor tissues. Then, cell proliferation, cell cycle, apoptosis, and migration of circRNA_100876-knocked down cells were analyzed by in vitro and in vivo experiments, using cell counting kit-8 (CCK-8), flow cytometry, and transwell and tumorigenesis assays. The expression of circRNA_100876 was found to be significantly upregulated in osteosarcoma, and was closely correlated with the tumor size and tumor differentiation degree. In addition, the knockdown of circRNA_100876 could significantly inhibit the tumor growth, both in vitro and in vivo. Flow cytometry and Western blot analysis results showed that the downregulation of circRNA_100876 inhibited osteosarcoma cells proliferation via promoting apoptosis and arresting more cells in the G2/M stage, as suggested by the expression of apoptosis and cell cycle pathway-related proteins, which changed consistently. Furthermore, the level of miR-136 was negatively correlated with the expression of circRNA_100876, and miR-136 inhibitors were able to reverse the suppression of cell proliferation induced by silencing circRNA_100876. Our study demonstrates that the dysregulation of circRNA_100876 could induce apoptosis and arrest the cell cycle at G2/M stage, followed by suppression of cell proliferation in osteosarcoma, while silencing miR-136 could restore the cell growth. Therefore, circRNA_100876 might serve as a promising biomarker and treatment target for osteosarcoma.