Identification of Novel miRNAs, Targeting Genes, Signaling Pathway, and the Small Molecule for Overcoming Oxaliplatin Resistance of Metastatic Colorectal Cancer

Abstract

One of the globally common cancers is colorectal cancer (CRC). At present, a surgical approach remains a good option for CRC patients; however, 20% of surgically treated CRC patients experience metastasis. Currently, even the first-line used drug, oxaliplatin, remains inadequate for treating metastatic CRC, and its side effect of neurotoxicity is a major problem when treating CRC. The Gene Omnibus GSE42387 database contains gene expression profiles of parental and oxaliplatin-resistant LoVo cell lines. Differentially expressed genes (DEGs) between parental and oxaliplatin-resistance LoVo cells, protein-protein interactions (PPIs), and a pathway analysis were determined to identify overall biological changes by an online DAVID bioinformatics analysis. The ability of DEGs to predict overall survival (OS) and disease-free survival (DFS) was validated by the SPSS 22.0, using liver metastasis CRC patient samples of GSE41258. The bioinformatics web tools of the GEPIA, the Human Protein Atlas, WebGestalt, and TIMER platforms were used. In total, 218 DEGs were identified, among which 105 were downregulated and 113 were upregulated. After mapping the PPI networks and pathways, 60 DEGs were identified as hub genes (with high degrees). Six genes (TGFB1, CD36, THBS1, FABP1, PCK1, and IRS1) were involved with malaria, PPAR signaling, and the adipocytokine signaling pathway. High expressions of CD36 and PCK1 were associated with the poor survival of CRC patients in the GSE41258 database. We predicted specific micro (mi)RNAs that targeted the 3 ′ untranslated region (UTR) of PCK1 by using miRWalk. It was found that three miRNAs, viz., miR-7-5p, miR-20a-3p, and miR-636, may be upstream targets of those genes. High expression levels of miR-7-5p, miR-20a-3p, and miR-636 were associated with poor OS of CRC patients, and the small-molecule compound, mersalyl, is a promising drug for treating oxaliplatin-resistant CRC. In conclusion, miR-7-5p miR-20a-3p, and miR-636 targeted the PCK1 biomarker in the PPAR signaling pathway, which is involved in oxaliplatin-resistant CRC. Meanwhile, mersalyl was identified as a potential drug for overcoming oxaliplatin resistance in CRC. Our findings may provide novel directions and strategies for CRC therapies.

Peroxisome proliferator-activated receptors: Key regulators of tumor progression and growth

“…PPARs play a critical role in the progression and prognosis of CRC, according to bioinformatics analysis of PPARs. Based on an investigation of the mechanisms of drug resistance and identifying biomarkers of colon cancer cell lines, Misbah et al found that PPAR signaling was enriched by different genes expression in colon cancer cell lines [ 161 ].…”

Role of miRNA in Cardiovascular Diseases in Children—Systematic Review

“…It is worth mentioning that so far miR-636, miR-639 and miR-646 have been mainly described as cancer-related miRNAs. Among others, they were reported to be associated with colon, gastric, ovarian, cervical, breast, endometrial, liver and thyroid cancers [83][84][85][86][87][88][89].…”

Peroxisome proliferator-activated receptors regulate the progression and treatment of gastrointestinal cancers

“…Systematic analysis of PPARs by bioinformatics has identified the critical roles of PPARs in the progression and prognosis of CRC. Md Misbah et al investigated the mechanisms of drug resistance and identified biomarkers of CRC in colon cancer cell lines, revealing PPAR signaling to be one of the pathways enriched by different expression genes ( Misbah et al, 2022 ). In addition, Ozlem Kurnaz et al confirmed that there is increased risk for patients with the PPARγ T161 allele in CRC development ( Kurnaz-Gomleksiz et al, 2022 ).…”