miR-۱۸۵-۵p potentially mitigates ۵-Fu/DPP chemoresistance via targeting SEZ۶L۲ in colorectal cancer

Colorectal cancer (CRC) generally arises from the colon or the rectum and can begin as benign polyps that could progress to malignant tumors. CRC is one of the most common types of cancer diagnosed around the world and is among the leading causes of cancer-related mortality. Chemoresistance remains one of the most serious complications encountered clinically in treating CRC. Identifying transcripts implicated in CRC chemoresistance is an important step toward understanding the basic mechanisms of resistance and the genes involved. In this study, we analyzed the difference in gene expression among chemosensitive (HCT۸) and chemoresistant [HCT۸/۵-fluorouracil (۵-Fu) and HCT۸/cisplatin (DDP)] cell lines. The high-throughput RNA sequencing data was retrieved from the Gene Expression Omnibus (GEO) database, Accession Number GSE۱۷۳۶۰۶. Then, it was analyzed through the Galaxy Europe web platform. Differential expression analysis was run using the Limma tool, Version ۳.۵۸.۱, between each DDP-resistant and ۵-Fu-resistant compared to sensitive samples. The top ۱۰۰ upregulated genes from each comparison were identified, and ۷۲ common upregulated genes were found. Among those genes, we found a significantly expressed SEZ۶L۲, associated with poor overall survival of CRC patients found in pan-cancer analysis based on data obtained from the ENCORI database. Moreover, previous studies have also pointed out that high levels of SEZ۶L۲ are associated with poor prognosis in patients with CRC and other cancers. MicroRNAs (miRNAs) are short, non-translatable RNAs, which increasingly play an important role in the process of gene expression. They play an essential role in regulating oncogenes in cancers by binding to specific regions of mRNAs and repressing their translation into proteins. This could lead to the reduction of tumor growth and cancer cell proliferation, making miRNAs ideal targets for cancer treatment. miRNAs highly associated with SEZ۶L۲ were further investigated, by which high-scoring miRNAs were obtained from TargetScan and miRWalk databases and has-miR-۱۸۵-۵p was chosen for further study. The miRNA-Target CoExpression analysis of The ENCORI database showed a negative relation expression between SEZ۶L۲ and miR-۱۸۵-۵p. Collectively, our study unveiled the potential predictive value of SEZ۶L۲ for ۵-Fu/DDP resistance in colorectal cancer and identified miR-۱۸۵-۵p as a prospective target of SEZ۶L۲ that might provide a therapeutic approach to the enhancement of CRC chemosensitivity by targeting SEZ۶L۲.

کلیدواژه ها:

colorectal cancer ، chemoresistance ، RNA seq ، Biomarker ، microRNA