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Identification of Circular RNAs Associated With Chemoresistance in Colorectal Cancer.

ABSTRACT: Chemoresistance is a major clinical obstacle for the treatment of colorectal cancer (CRC). Circular RNAs (circRNAs) are a new type of non-coding RNA that participated in the development of chemoresistance. However, the profiles and effects of circRNAs in 5-fluorouracil (5-Fu) and cisplatin resistance of CRC are still unclear and need to be elucidated. In the present study, the profiles of circRNAs in CRC chemoresistant (HCT8/5-Fu and HCT8/DDP) and chemosensitive (HCT8) cell lines were identified via RNA-sequencing. In total, 48 and 90 differentially expressed (DE)-circRNAs were detected in HCT8/5-Fu and HCT8/DDP cell lines, respectively. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted on the host genes of DE-circRNAs; the results showed that the most significant enrichment pathways in HCT8/5-Fu and HCT8/DDP cell lines were base excision repair and Hippo signaling pathway, respectively. In addition, 11 common DE-circRNAs in the two drug-resistant cell lines (two are upregulated and nine are downregulated) were screened and verified by quantitative real-time PCR; hsacirc_023607 and hsacirc_007420 were found to be the circRNAs with the highest upregulation and downregulation fold changes. However, functional studies showed hsacirc_023607 has no effect on CRC chemoresistance. Therefore, the regulatory networks of targeted miRNAs related to 5-Fu or cisplatin resistance were predicted and constructed, in which hsacirc_002482 was identified as a hub gene, and its overexpression could suppress HCT8/5-Fu and HCT8/DDP cell proliferation and promote cell apoptosis, and enhance cell chemosensitivity. Taken together, these results of the study suggested that hsacirc_002482 may play important roles in chemoresistance of CRC.

SUBMITTER: Yao F

PROVIDER: S-EPMC8484910 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: circRNAs, a recently identified new member of non-coding RNAs, have been proved to play an essential role in the development and progression of various cancers. However, the functions and mechanisms of circRNAs in colorectal liver metastasis have not been fully elucidated. Methods: We performed circRNA microarray to screen differentially expressed novel circRNAs in the pathology of colorectal liver metastasis. Quantitative real-time PCR was used to detect the circ102049 expression in colorectal cancer (CRC) samples. Then CRC cells were transfected with a circ102049 over-expression vector or siRNAs, and the effects of circ102049 on biological functions in CRC cells were accessed in vitro. Mechanistically, the bioinformatics analysis, fluorescence in situ hybridization, RIP assay, RNA pull down assay and luciferase reporter assay were conducted to confirm the relationships among circ102049, miR-761, miR-192-3p and FRAS1. Moreover, the mechanism of circ102049 how to recruit and distribute DGCR8 protein in cytoplasm was elucidated. Results: The results showed that circ102049 was highly expressed in primary CRC tumors with liver metastasis and closely correlated with the CRC patients' prognosis. Circ102049 might act as a novel metastasis-related non-coding RNA, and significantly promote the adhesion, migration and invasion abilities of CRC cells. Mechanistically, we verified that circ102049 promoted the CRC development and progression via a miR-761/miR-192-3p-FRAS1-dependent mechanism. Notably, due to the distribution of DGCR8 protein, circ102049 might also reduce the mature products of miR-761 and miR-192-3p in cytoplasm indirectly. In addition, the role of circ102049 in promoting colorectal liver metastasis was also confirmed in vivo. Conclusions: Our findings provided new clues that circ102049 might be a potential prognostic factor in CRC, and the circ102049-miR-761/miR-192-3p-FRAS1 axis could be further explored as a therapeutic target for anti-metastatic therapy in CRC patients with liver metastases. Keywords: Hsa_circ_102049, miR-761, miR-192-3p, FRAS1, Colorectal liver metastasis

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Identification of Circular RNAs Associated With Chemoresistance in Colorectal Cancer.

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