In silico analysis to identify miR-1271-5p/PLCB4 (phospholipase C Beta 4) axis mediated oxaliplatin resistance in metastatic colorectal cancer
Abstract Oxaliplatin (OXA) is the first-line chemotherapy drug for metastatic colorectal cancer (mCRC), and the emergence of drug resistance is a major clinical challenge. Although there have been numerous studies on OXA resistance, but its underlying molecular mechanisms are still unclear. This stu...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-03-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-31331-2 |
| _version_ | 1797864921309904896 |
|---|---|
| author | Cheng-Chin Lee Ai-Wei Lee Po-Li Wei Yi-Shin Liu Yu-Jia Chang Chien-Yu Huang |
| author_facet | Cheng-Chin Lee Ai-Wei Lee Po-Li Wei Yi-Shin Liu Yu-Jia Chang Chien-Yu Huang |
| author_sort | Cheng-Chin Lee |
| collection | DOAJ |
| description | Abstract Oxaliplatin (OXA) is the first-line chemotherapy drug for metastatic colorectal cancer (mCRC), and the emergence of drug resistance is a major clinical challenge. Although there have been numerous studies on OXA resistance, but its underlying molecular mechanisms are still unclear. This study aims to identify key regulatory genes and pathways associated with OXA resistance. The Gene Expression Omnibus (GEO) GSE42387 dataset containing gene expression profiles of parental and OXA-resistant LoVo cells was applied to explore potential targets. GEO2R, STRING, CytoNCA (a plug-in of Cytoscape), and DAVID were used to analyze differentially expressed genes (DEGs), protein–protein interactions (PPIs), hub genes in PPIs, and gene ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. R2 online platform was used to run a survival analysis of validated hub genes enriched in KEGG pathways. The ENCORI database predicted microRNAs for candidate genes. A survival analysis of those genes was performed, and validated using the OncoLnc database. In addition, the 'clusterProfiler' package in R was used to perform gene set enrichment analysis (GSEA). We identified 395 DEGs, among which 155 were upregulated and 240 were downregulated. In total, 95 DEGs were screened as hub genes after constructing the PPI networks. Twelve GO terms and three KEGG pathways (steroid hormone biosynthesis, malaria, and pathways in cancer) were identified as being significant in the enrichment analysis of hub genes. Twenty-one hub genes enriched in KEGG pathways were defined as key genes. Among them AKT3, phospholipase C Beta 4 (PLCB4), and TGFB1 were identified as OXA-resistance genes through the survival analysis. High expressions of AKT3 and TGFB1 were each associated with a poor prognosis, and lower expression of PLCB4 was correlated with worse survival. Further, high levels of hsa-miR-1271-5p, which potentially targets PLCB4, were associated with poor overall survival in patients with CRC. Finally, we found that PLCB4 low expression was associated with MAPK signaling pathway and VEGF signaling pathway in CRC. Our results demonstrated that hsa-miR-1271-5p/PLCB4 in the pathway in cancer could be a new potential therapeutic target for mCRC with OXA resistance. |
| first_indexed | 2024-04-09T22:59:43Z |
| format | Article |
| id | doaj.art-9992e26a38904245902a128b908ce19d |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-09T22:59:43Z |
| publishDate | 2023-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-9992e26a38904245902a128b908ce19d2023-03-22T11:03:57ZengNature PortfolioScientific Reports2045-23222023-03-0113111710.1038/s41598-023-31331-2In silico analysis to identify miR-1271-5p/PLCB4 (phospholipase C Beta 4) axis mediated oxaliplatin resistance in metastatic colorectal cancerCheng-Chin Lee0Ai-Wei Lee1Po-Li Wei2Yi-Shin Liu3Yu-Jia Chang4Chien-Yu Huang5Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityDepartment of Surgery, School of Medicine, College of Medicine, Taipei Medical UniversityGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical UniversitySchool of Medicine, National Tsing Hua UniversityAbstract Oxaliplatin (OXA) is the first-line chemotherapy drug for metastatic colorectal cancer (mCRC), and the emergence of drug resistance is a major clinical challenge. Although there have been numerous studies on OXA resistance, but its underlying molecular mechanisms are still unclear. This study aims to identify key regulatory genes and pathways associated with OXA resistance. The Gene Expression Omnibus (GEO) GSE42387 dataset containing gene expression profiles of parental and OXA-resistant LoVo cells was applied to explore potential targets. GEO2R, STRING, CytoNCA (a plug-in of Cytoscape), and DAVID were used to analyze differentially expressed genes (DEGs), protein–protein interactions (PPIs), hub genes in PPIs, and gene ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. R2 online platform was used to run a survival analysis of validated hub genes enriched in KEGG pathways. The ENCORI database predicted microRNAs for candidate genes. A survival analysis of those genes was performed, and validated using the OncoLnc database. In addition, the 'clusterProfiler' package in R was used to perform gene set enrichment analysis (GSEA). We identified 395 DEGs, among which 155 were upregulated and 240 were downregulated. In total, 95 DEGs were screened as hub genes after constructing the PPI networks. Twelve GO terms and three KEGG pathways (steroid hormone biosynthesis, malaria, and pathways in cancer) were identified as being significant in the enrichment analysis of hub genes. Twenty-one hub genes enriched in KEGG pathways were defined as key genes. Among them AKT3, phospholipase C Beta 4 (PLCB4), and TGFB1 were identified as OXA-resistance genes through the survival analysis. High expressions of AKT3 and TGFB1 were each associated with a poor prognosis, and lower expression of PLCB4 was correlated with worse survival. Further, high levels of hsa-miR-1271-5p, which potentially targets PLCB4, were associated with poor overall survival in patients with CRC. Finally, we found that PLCB4 low expression was associated with MAPK signaling pathway and VEGF signaling pathway in CRC. Our results demonstrated that hsa-miR-1271-5p/PLCB4 in the pathway in cancer could be a new potential therapeutic target for mCRC with OXA resistance.https://doi.org/10.1038/s41598-023-31331-2 |
| spellingShingle | Cheng-Chin Lee Ai-Wei Lee Po-Li Wei Yi-Shin Liu Yu-Jia Chang Chien-Yu Huang In silico analysis to identify miR-1271-5p/PLCB4 (phospholipase C Beta 4) axis mediated oxaliplatin resistance in metastatic colorectal cancer Scientific Reports |
| title | In silico analysis to identify miR-1271-5p/PLCB4 (phospholipase C Beta 4) axis mediated oxaliplatin resistance in metastatic colorectal cancer |
| title_full | In silico analysis to identify miR-1271-5p/PLCB4 (phospholipase C Beta 4) axis mediated oxaliplatin resistance in metastatic colorectal cancer |
| title_fullStr | In silico analysis to identify miR-1271-5p/PLCB4 (phospholipase C Beta 4) axis mediated oxaliplatin resistance in metastatic colorectal cancer |
| title_full_unstemmed | In silico analysis to identify miR-1271-5p/PLCB4 (phospholipase C Beta 4) axis mediated oxaliplatin resistance in metastatic colorectal cancer |
| title_short | In silico analysis to identify miR-1271-5p/PLCB4 (phospholipase C Beta 4) axis mediated oxaliplatin resistance in metastatic colorectal cancer |
| title_sort | in silico analysis to identify mir 1271 5p plcb4 phospholipase c beta 4 axis mediated oxaliplatin resistance in metastatic colorectal cancer |
| url | https://doi.org/10.1038/s41598-023-31331-2 |
| work_keys_str_mv | AT chengchinlee insilicoanalysistoidentifymir12715pplcb4phospholipasecbeta4axismediatedoxaliplatinresistanceinmetastaticcolorectalcancer AT aiweilee insilicoanalysistoidentifymir12715pplcb4phospholipasecbeta4axismediatedoxaliplatinresistanceinmetastaticcolorectalcancer AT poliwei insilicoanalysistoidentifymir12715pplcb4phospholipasecbeta4axismediatedoxaliplatinresistanceinmetastaticcolorectalcancer AT yishinliu insilicoanalysistoidentifymir12715pplcb4phospholipasecbeta4axismediatedoxaliplatinresistanceinmetastaticcolorectalcancer AT yujiachang insilicoanalysistoidentifymir12715pplcb4phospholipasecbeta4axismediatedoxaliplatinresistanceinmetastaticcolorectalcancer AT chienyuhuang insilicoanalysistoidentifymir12715pplcb4phospholipasecbeta4axismediatedoxaliplatinresistanceinmetastaticcolorectalcancer |