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RNA-Seq profiling of circular RNAs in human colorectal cancer 5-fluorouracil resistance and the potential biomarkers

ABSTRACT: Colorectal cancer（CRC）is a commonly diagnosed cancer of the digestive system worldwide. Although chemotherapeutic agents and targeted therapeutic drugs are currently available for CRC treatment, drug resistance is a problem that cannot be ignored and needs to be solved. 5-Fluorouracil (5-Fu) is a first-line chemotherapeutic agent for colorectal cancer, to explore the role of circular RNA (circRNA) in 5-Fu resistance, we performed the circRNA expression profile in two CRC cell lines and their homologous 5-Fu resistant cells by high-throughput sequencing. We validated the differentially expressed circRNAs in other two paired CRC cells, confirmed that circ_0002813 and circ_0000236 could have a potential ceRNA mechanism and be involved in the formation of 5-Fu resistance. And we combined the sequencing results of mRNA to construct the regulatory network of circRNA-miRNA-mRNA. Our study revealed that circ_0002813 and circ_0000236 may as the biomarkers to predict the occurrence of 5-Fu resistance in CRC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE181537 | GEO | 2024/08/05

REPOSITORIES: GEO

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Project description:Background: Colorectal cancer is the third most common and the fourth most lethal cancer in the world. In the majority of cases, patients are diagnosed at an advanced stage or even metastatic, thus explaining the high mortality. The standard protocol for treating patients with locally advanced non-metastatic colorectal cancer (CRC) is neoadjuvant radio-chemotherapy (NRCT) with 5-fluorouracil (5-FU), but the resistance rate to this treatment remains high with approximately 30% of non-responders. The lack of evidence available in clinical practice to predict NRCT resistance to 5-FU and to guide clinical practice therefore encourages the search for biomarkers of this resistance. Methods: From twenty-three formalin-fixed paraffin-embedded (FFPE) biopsies performed before NRCT with 5-FU of locally advanced non-metastatic CRC patients, we extracted and analysed the tumor proteome of these patients. From clinical data, we were able to classify the twenty-two patients in our cohort into three treatment response groups: non-responders (NR), partial responders (PR) and total responders (TR), and to compare the proteomes of these different groups. Results: We have highlighted 384 differentially expressed proteins between NR and PR, 248 between NR and TR and 417 between PR and TR. Among these proteins, we have identified many differentially expressed proteins identified as having a role in cancer (IFIT1, FASTKD2, PIP4K2B, ARID1B, SLC25A33: overexpressed in TR; CALD1, CPA3, B3GALT5, CD177, RIPK1: overexpressed in NR). We have also identified that DPYD, the main degradation enzyme of 5-FU, was overexpressed in NR, as well as several ribosomal and mitochondrial proteins also overexpressed in NR. Conclusions: From these retrospective study, we implemented a protein extraction protocol from FFPE biopsy to highlight protein differences between different response groups to RCTN with 5-FU in patients with locally advanced non-metastatic CRC. These results will pave the way for a larger cohort for better sensitivity and specificity of the signature to guide decisions in the choice of treatment.

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RNA-Seq profiling of circular RNAs in human colorectal cancer 5-fluorouracil resistance and the potential biomarkers

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