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.
Highlights
Colorectal cancer (CRC) is a common malignant tumor of the digestive system, with high morbidity and mortality (Bray et al, 2018)
CircRNASORE could bind with the oncogenic protein YBX1 in the cytoplasm, preventing YBX1 degradation mediated by PRP19; sorafenib resistance was overcame when silencing circRNASORE (Xu et al, 2020)
The results showed that the cell viability of all groups decreased with the concentration of the drug increased
Summary
Colorectal cancer (CRC) is a common malignant tumor of the digestive system, with high morbidity and mortality (Bray et al, 2018). A deeper understanding and exploration of mechanisms of chemoresistance are crucial to improve the efficacy of chemotherapy in CRC. The development of high-throughput technology provides the possibility for indepth study of circRNAs. Accumulating evidence demonstrated that circRNAs were involved in numerous biological processes (BPs), such as cell proliferation, apoptosis, invasion, and migration and related to the chemoresistance of various cancers (Salzman, 2016; Jeyaraman et al, 2019; Wang et al, 2019). CircRNASORE could bind with the oncogenic protein YBX1 in the cytoplasm, preventing YBX1 degradation mediated by PRP19; sorafenib resistance was overcame when silencing circRNASORE (Xu et al, 2020). These studies indicated circRNAs may play important regulatory roles in cancer chemoresistance. The expression profiles and effects of circRNAs in 5Fu and cisplatin resistance of CRC are still unclear and need to be elucidated
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