Identification of circular RNA hsa_circ_0044556 and its effect on the progression of colorectal cancer

**g, Liang; Wu, Junhui; Tang, **aocheng; Ma, Min; Long, Fei; Tian, Buning; Lin, Changwei

doi:10.1186/s12935-020-01523-1

Identification of circular RNA hsa_circ_0044556 and its effect on the progression of colorectal cancer

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Published: 01 September 2020

Volume 20, article number 427, (2020)
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Identification of circular RNA hsa_circ_0044556 and its effect on the progression of colorectal cancer

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Liang **g¹,
Junhui Wu¹,
**aocheng Tang¹,
Min Ma¹,
Fei Long¹,
Buning Tian ORCID: orcid.org/0000-0003-4488-2597¹ &
…
Changwei Lin¹

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Abstract

Background

Circular RNAs (circRNAs) are a novel class of noncoding RNAs. Increasing evidence indicates that circRNAs play an important role in the occurrence and development of tumors. However, the role of circRNA hsa_circ_0044556 in the progression of colorectal cancer (CRC) remains unclear.

Methods

First, we searched for differentially expressed circRNAs using a circRNA microarray in paired CRC and adjacent normal tissues. The circRNA hsa_circ_0044556 was screened out from the existing CRC circRNA microarray in the Gene Expression Omnibus database and our microarray. The clinical significance of hsa_circ_0044556 expression level in CRC patients was then investigated. Finally, the functions of the targets of this circRNA were determined in CRC cell lines.

Results

Hsa_circ_0044556 was highly expressed in CRC patients and was positively correlated with tumor stage and lymph node metastasis. In CRC cell lines, the proliferation, migration, and invasion of cancer cells were inhibited by knocking down hsa_circ_0044556 expression.

Conclusion

Hsa_circ_0044556 promoted the progression of CRC. It is possible that hsa_circ_0044556 will become a novel biomarker or therapeutic target for CRC.

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Background

Colorectal cancer (CRC) is a malignant cancer that seriously endangers the health of humans. Currently, the global incidence rate of CRC ranks third among cancer-related diseases with up to 1.2 million new cases each year, and more than 0.6 million deaths are expected each year [1]. From the perspective of the global incidence trend, the European and American regions are higher than the Asian and African regions, with the second place mortality rate (9.2%), and the develo** countries are higher than the developed countries [2]. In 2015, China's cancer statistics showed that the incidence and the mortality of CRC ranked fifth among cancer-related diseases in China. The incidence of CRC and the death toll are rising yearly while the population with this disease trends younger [3]. Early diagnosis, accurate prognosis, and recurrence monitoring play important roles in cancer diagnosis and treatment. The 5-year survival rate of patients with advanced CRC is only 12%, while the 5-year survival rate of patients at the early stage can reach more than 90% [4]. Therefore, early diagnosis can significantly improve the prognosis as well as the survival and quality of life of patients with CRC. On this basis, the in-depth study of the pathophysiology mechanisms underlying the occurrence and development of CRC will help us more comprehensively understand this cancer and open up new ideas and methods for the diagnosis and treatment of CRC. However, accurate and reliable prognosis and recurrence monitoring methods for CRC patients are still lacking in clinical practice, which makes it impossible to perform detailed posttreatment management and recurrence monitoring for patients [5, 6].

Circular RNAs (circRNAs) are a new class of noncoding RNAs (ncRNAs), which are single-stranded circular RNAs with no free 5′-end cap or 3′-end poly (A) tail. They are produced by alternative splicing of a specific pre-mRNA (pre-mRNA). Most circRNAs consist of exons and may also contain intergenic or noncoding regions [7,8,9,10]. CircRNAs did not attract much attention from researchers at first. For a long time, circRNAs were considered by-products of incorrect alternative splicing. Then in 2012, Salzman et al. discovered a large number of circRNAs using high-throughput sequencing technology [7]. Now it is recognized that circRNAs are not as rare as previously thought. In contrast, circRNAs are highly stable in cells with high expression, and sometimes their expression levels are even 10 times higher than those of their homologous messenger RNAs. It has been found that circRNAs can act as a miRNA sponge bound to RNA-binding protein to exert biological functions.

In recent years, circRNAs have been considered to play an important role in tumor progression [11]. CircRNAs are expected to become biomarkers for tumor diagnosis and prognosis due to their stable circular structure [12]. Xu et al. found that hsa_circ_0001649 was expressed at abnormally low levels in intrahepatic cholangiocarcinoma tissues and could promote cell proliferation and tumor metastasis [13]. Circ-ITCH can act as a sponge of miR-7 and miR-20a to inhibit the negative regulatory effect of the latter on the target gene ITCH, while ITCH has a tumor suppressor function by inhibition of the Wnt/β-catenin signaling pathway [14]. However, the role of circRNA hsa_circ_0044556 in CRC remains unclear and deserves further investigation.

Materials and methods

Tissue collection

In this study, tissue samples of 52 patients with CRC from the Third ** set predicted by databases of miRDB [Full size image

Bioinformatic analysis of the predicted genes in hsa_circ_0044556

Gene ontology (GO) analysis was performed on hsa_circ_0044556, and the functional roles of the top 10 most enriched target genes were investigated from the perspective of biological processes (Fig. 6a). The results showed that hsa_circ_0044556 had a strong correlation with the cell cycle, responses to steroid hormone stimulation, and angiogenesis. KEGG analysis of hsa_circ_0044556 indicated that its top nine enriched pathways included prostate cancer, the cancer pathway, and the ErbB signaling pathway (Fig. 6b). Seven target genes were enriched in the cancer pathway. These data suggested that hsa_circ_0044556 may play important roles in the malignant behavior of cancer by regulating the expression of target genes involved in these pathways.

Discussion

In recent years, with the rapid development and extensive application of RNA sequencing technology, circRNAs have become a hotspot in the field of RNA research. Researchers have found that many exon transcripts can form circRNAs through nonlinear reverse splicing or gene rearrangement. Moreover, they account for a large percentage of all spliced transcripts [7]. CircRNAs may come from introns or exons [28]. In mammals, exon-constituted circRNAs have two mechanisms of loop formation: lariat-driven circularization and intron-pairing-driven circularization [7, 29, 30]. A covalently closed circular structure without a 5′-to-3′ polarity or poly(A) tail is then formed by reverse splicing of a typical splice.

More and more studies have investigated the potential functions of circRNAs in various diseases, such as nervous system diseases, cardiovascular diseases, and cancers [31,32,33,34]. Some abnormally expressed circRNAs have been associated with the tumor development, invasion, metastasis, or prognosis of patients [35,36,37,38,39,40,41]. In mammalian cells, compared with other ncRNAs, such as miRNAs and long noncoding RNAs, circRNAs have highly conserved sequences and high stability [42]. These features might let circRNAs become ideal biomarkers and potential therapeutic targets for disease diagnosis.

In this study, high-throughput circRNA microarrays were used to study the expression of circRNAs in human CRC. The results showed that the expression of circRNAs in CRC tissues (n = 3) was significantly different from that in adjacent normal tissues (n = 3) (Fig. 1). Compared with the adjacent normal tissues, our microarray data showed that 66 circRNAs were significantly upregulated while 77 circRNAs were significantly downregulated in CRC tissues (Additional file 1: Table S1). We verified the expression levels of two circRNAs (hsa_circ_0004104 and hsa_circ_0044556) in 10 pairs of CRC and adjacent normal tissue samples, and only hsa_circ_0044556 was determined to be upregulated in CRC tissues, and with statistical significance (P = 0.0304) (S Additional file 2: Figure S1A). The expression level of hsa_circ_0004104 was inconsistent with the microarray results, and there was no statistical significance (P = 0.9208) (Additional file 2: Figure S1B). The above results indicate that validation of differently expressed circRNAs in microarray analysis is an important step in such a screening study. In addition, to verify the results above, we expanded the sample size to detect the expression of hsa_circ_0044556 in other tissue samples (n = 52). The results showed that hsa_circ_0044556 was significantly upregulated in 69.23% (36/52) of CRC tissues, with an average increase of 6.65-fold compared to the adjacent normal tissues. ROC analysis showed that hsa_circ_0044556 level had relatively high sensitivity and specificity, with an AUC of 0.7274 (Fig. 2). More importantly, considering the clinical pathological factors, we found that the high expression level of hsa_circ_0044556 in CRC was closely related to tumor stage and lymph node metastasis (Table 2), important factors in evaluating the prognosis of CRC. These results indicate that hsa_circ_0044556 might be involved in the progression and metastasis of CRC and could be used as a potential biomarker and a new therapeutic target for CRC.

One of the most important things about circRNAs is that they act as miRNA sponges. Certain specific circRNAs can bind and negatively regulate miRNAs involved in the competitive endogenous RNA (ceRNA) network, thereby regulating linear RNA transcription and protein production. Thomas et al. found that circRNA ciRS-7 can strongly inhibit miR-7 activity, leading to increased miR-7 target expression levels [40, 43]. Other functions may include gene expression regulation at the transcriptional or posttranscriptional level [44], and even encoding proteins [45, 46]. In this study, to further understand the biological functions of hsa_circ_0044556, 5 miRNAs with the highest mirSVR scores were identifed for each differentially expressed circRNA using miRNA target-prediction sofware (namely, hsa-mir-214-3p, hsa-mir-761, hsa-mir-194-3p, hsa-mir-412-3p, and hsa-mir-362-5p) (Additional file 1: Table S1). We used TargetScan, miRDB, and miRTarBase to predict the hsa_circ_0044556-miRNA–mRNA network. In essence, this network diagram shows a cellular RNA network with hsa_circ_0044556 interacting with 5 miRNA nodes and 107 target genes (Fig. 5b). Through the retrieval of ENCORI and UALCAN, it was found that hsa-mir-214-3p had low expression in colorectal adenocarcinoma. Furthermore, it have been found that hsa-mir-214-3p was significantly reduced in epithelial ovarian cancer cells and could affect epithelial ovarian cancer cell proliferation, invasion, increasing cisplatin chemosensitivity and inhibiting in vivo tumor growth proliferation by binding X-inactive specific transcript (XIST) [47]. It have also been reported that the downregulated hsa-miR-145-5p and hsa-mir-214-3p may modulate the expression of both EMT and NGAL/MMP-9 pathways [48]. In CRC lines, we also confirmed that silencing the expression level of hsa_circ_0044556 increased the expression level of hsa-mir-214-3p. Therefore, the decreased expression and inhibited function of hsa-mir-214-3p in CRC further support our hypothesis that hsa_circ_0044556 functions as a miRNA sponge to regulate the hsa_circ_0044556- hsa-mir-214-3p-mRNA network.

We found that a large number of mRNAs may participate in the above hsa_circ_0044556-miRNA–mRNA network, such as ARL2, MAPK1, and PTEN. Therefore, GO and KEGG pathway analysis was performed to detect the functions of these potential target genes. The results of GO enrichment analysis (Fig. 6a) showed that the target genes of hsa_circ_0044556 participated in the regulation of the cell cycle and angiogenesis, indicating that the regulation of these genes in the occurrence and development of CRC has importance in cell responses. The cancer pathway and the ErbB signaling pathway, two KEGG pathways correlated with hsa_circ_0044556 expression (Fig. 6b), may be related to the proliferation, migration, and invasion of CRC cells. Therefore, we speculate that the hsa_circ_0044556-miRNA–mRNA axis is a possible mechanism that promotes the development of CRC, and it is worthwhile to further study the overexpression of hsa_circ_0044556 as an inhibitor of miRNA and its possible mechanism of action.

In summary, this study revealed the expression profile of circRNAs in CRC tissues and demonstrated the abnormal expression of circRNAs in CRC. This study confirmed the significance of the upregulation of hsa_circ_0044556 and analyzed the relationship between hsa_circ_0044556 and the clinicopathological features of CRC patients, suggesting its potential role in the development and progression of CRC and its potential application as a CRC diagnostic biomarker. In the future, it will be necessary to explore the molecular mechanism of hsa_circ_0044556 as a miRNA sponge regulating the development and progression of CRC.

Conclusion

Hsa_circ_0044556 promoted the progression of CRC. It is possible that hsa_circ_0044556 will become a new biomarker or therapeutic target for CRC.

Data availability statement

All datasets presented in this study are included in the article/additional files.

Abbreviations

ARL2:: ADP ribosylation factor-like protein 2
ANOVA:: Analysis of Variance
cDNA:: Complementary DNA
CEA:: Carcinoembryonic antigen
circRNAs:: Circular RNAs
COL1A1:: Collagen type 1 alpha 1
CRC:: Colorectal cancer
DAVID:: The Database for Annotation Visualization and Integrated Discovery
DMEM:: Dulbecco's Modified Eagle Medium
DNA:: Deoxyribonucleic acid
ENCORI:: The Encyclopedia of RNA Interactomes
FBS:: Fetal bovine serum
GAPDH:: Glyceraldehyde phosphate dehydrogenase
GEO:: Gene expression omnibus
GO:: Gene Ontology
ITCH:: Itchy E3 ubiquitin protein ligase
KEGG:: Kyoto Encyclopedia of Genes and Genomes
MAPK1:: Mitogen activated protein kinase 1
miRNA:: MicroRNA
mRNA:: Messenger RNA
NC:: Negative control
ncRNAs:: Noncoding RNAs
OB:: Occult blood
ROC:: Receiver operating characteristic
PBS:: Phosphate buffered saline
PCR:: Polymerase chain reaction
PTEN:: Phosphatase and tensin homolog
RT-qPCR:: Reverse transcription and real-time quantitative PCR
RNA:: Ribonucleic acid
siRNA:: Small interfering RNA
shRNA:: Short hairpin RNA
SPSS:: Statistical Product and Service Solutions
TCGA:: The Cancer Genome Atlas

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Acknowledgments

The authors wish to acknowledge the technical assistance of KangChen Bio-tech, Shanghai, China for Microarray experiments.

Funding

This work was supported by the Hunan Province Technological Innovation Guidance Program Foundation (No. S2017SFYLJS0274) and The Hunan Province Natural Science Foundation (No.2016JJ2155).

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Authors and Affiliations

Department of Gastrointestinal Surgery, The Third **angya Hospital of Central South University, Changsha, Hunan, China
Liang **g, Junhui Wu, **aocheng Tang, Min Ma, Fei Long, Buning Tian & Changwei Lin

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Liang **g
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Junhui Wu
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**aocheng Tang
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Min Ma
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Fei Long
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Buning Tian
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Changwei Lin
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Contributions

Experiments were designed by CL ang BT and were performed by LJ, MM, FL. XT analyzed data. JW interpreted results of experiments. The manuscript was written by LJ and JW and edited by CL and BT. All authors read and approved the final manuscript

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Correspondence to Buning Tian or Changwei Lin.

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The study which including human and animal approval were acquired from the Ethics Committee of The Third **angya Hospital of Central South University [Lot 2016-S086].

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Supplementary information

Additional file 1: Tables S1.

Results of circRNAs expression microarray in CRC.

Additional file 2: Figure S1.

The expression levels of has_circ_0044556 and has_circ_0004104 in CRC were preliminarily verified.

Additional file 3: Table S2.

Hsa_circ_0044556 common target genes in miRDB, miRTarBase and TargetScan.

Additional file 4: Figure S2.

The expression levels of has-mir-214-3p in the CRC tissues and adjacent normal tissues.

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**g, L., Wu, J., Tang, X. et al. Identification of circular RNA hsa_circ_0044556 and its effect on the progression of colorectal cancer. Cancer Cell Int 20, 427 (2020). https://doi.org/10.1186/s12935-020-01523-1

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Received: 07 May 2020
Accepted: 26 August 2020
Published: 01 September 2020
DOI: https://doi.org/10.1186/s12935-020-01523-1

Identification of circular RNA hsa_circ_0044556 and its effect on the progression of colorectal cancer

Abstract

Background

Methods

Results

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Materials and methods

Tissue collection

Bioinformatic analysis of the predicted genes in hsa_circ_0044556

Discussion

Conclusion

Data availability statement

Abbreviations

References

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