Published online Apr 16, 2022. doi: 10.12998/wjcc.v10.i11.3352
Peer-review started: October 29, 2021
First decision: December 27, 2021
Revised: December 30, 2021
Accepted: February 12, 2022
Article in press: February 12, 2022
Published online: April 16, 2022
Colorectal cancer (CRC) imposes a tremendous burden on human health, with high morbidity and mortality. Circular ribonucleic acids (circRNAs), a new type of noncoding RNA, are considered to participate in cancer pathogenesis as microRNA (miRNA) sponges. However, the dysregulation and biological functions of circRNAs in CRC remain to be explored.
To identify potential circRNA biomarkers of CRC and explore their functions in CRC carcinogenesis.
CircRNAs and miRNAs differentially expressed in CRC tissues were identified by analyzing expression profiles from the Gene Expression Omnibus (GEO) database. Circ_0000375 and circ_0011536 were selected as CRC biomarker candidates. Quantitative real-time polymerase chain reaction was utilized to evaluate the expression of these 2 circRNAs in CRC tissues, serums and cell lines. Receiver operating characteristic curves were generated to assess the diagnostic performances of these 2 circRNAs. Then, functional experiments, including cell counting kit-8, wound healing and Transwell invasion assays, were performed after the overexpression of circ_0000375 and circ_0011536 in CRC cell lines. Furthermore, candidate target miRNAs of circ_0000375 and circ_0011536 were predicted via bioinformatics analysis. The expression levels of these miRNAs were explored in CRC cell lines and tissues from GEO datasets. A luciferase reporter assay was developed to examine the interactions between circRNAs and miRNAs. Based on the target miRNAs and downstream genes, functional enrichment analyses were applied to reveal the critical signaling pathways involved in CRC carcinogenesis.
Downregulated circ_0000375 and circ_0011536 expression was observed in CRC tissues in GSE126095, clinical CRC tissue and serum samples and CRC cell lines. The areas under the curve for circ_0000375 and circ_0011536 were 0.911 and 0.885 in CRC tissue and 0.976 and 0.982 in CRC serum, respectively. Moreover, the serum levels of these 2 circRNAs were higher in patients at 30 d postsurgery than in patients before surgery, suggesting that the serum expression of circ_0000375 and circ_0011536 is related to CRC tumorigenesis. Circ_0000375 and circ_0011536 overexpression inhibited the proliferation, migration and invasion of CRC cells. Furthermore, miR-1182 and miR-1246, which were overexpressed in CRC tissues in GSE41655, GSE49246 and GSE115513, were verified as target miRNAs of circ_0000375 and circ_0011536, respectively, by luciferase reporter assays. The downstream genes of miR-1182 and miR-1246 were enriched in some CRC-associated pathways, such as the Wnt signaling pathway.
Circ_0000375 and circ_0011536 may function as tumor suppressors in CRC progression, serving as novel biomarkers for CRC diagnosis and as promising candidates for therapeutic exploration.
Core Tip: The dysregulation and biological functions of circular ribonucleic acids (circRNAs) in colorectal cancer (CRC) have not been well elucidated. In this study, circ_0000375 and circ_0011536 were observed to be downregulated in CRC tissues, serum samples and cell lines. These 2 circRNAs were validated as biomarker candidates in tissues and serum samples with high diagnostic performance. Overexpression of circ_0000375 and circ_0011536 inhibited the growth, migration and invasion of CRC cells. Furthermore, miR-1182 and miR-1246 were upregulated in CRC tissues as target microRNA of circ_0000375 and circ_0011536, respectively. Overall, circ_0000375 and circ_0011536 may serve as diagnostic biomarkers and function as tumor suppressors in CRC.