Bioinformatics screening of therapeutic targets in chemoresistance human colon cancer HCT8 cell line
Abstract
Background: Chemoresistance is still one of the main challenges in treatment of cancers, including colon adenocarcinoma (COAD). COAD is a common cancer with a high mortality. The goal of this study was to identify and evaluate the differentially expressed mRNAs (DEmRNAs) associated with both 5-fluorouracil (5-Fu) and cisplatin (DDP) resistance in human COAD cell line. Methods: Common DEmRNAs, DEmiRNAs, and DElncRNAs were obtained from the gene expression profile GSE173606 between acquired two chemoresistance (5-Fu and DDP) and sensitive HCT8 cells. PPI network of overlapped DEmRNAs was obtained based on STRING database and Cytoscape software. miRTarBase database was used to find DEmiRNAs which target the DEmRNAs. Then DElncRNAs which have interaction with the selected DEmiRNAs were obtained from RNAInter database. LncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) network visualized using Cytoscape software. Results: A high number of common DEmRNAs (about 1780) in chemoresistance HCT8 cells were identified. TIMER2.0 database showed that the expression of upregulated hub genes, including EGFR, TGFB1, ESR1, ICAM1, PECAM1, CAV1, and CCL5 has significant positive correlations with tumor infiltration of cancer-associated fibroblasts in COAD. CeRNA networks included the low expressed mRNAs (as targets of upregulated miR-675-3p, miR-6084, and miR-1182) whose expression is also downregulated in COAD tissues based on GEPIA database. MDM2 (as a target of downregulated miR-4635 and miR-4306) was an upregulated gene in both chemoresistance cells and COAD tumor tissues. RNAactDrug database confirmed the association of the high expression of four mRNAs of the ceRNA network (i.e., EFNB2, F2RL2, FLT1, and ADGRF1) with decreased drug sensitivity of DDP. Conclusion: The results of this study can offer therapeutic targets. For example, inhibition of CCL5, oncogenic miR-675-3p, and MDM2 might be a good choice for gene targeted therapy to overcome the multi-drug resistance in COAD. Moreover, it can provide multiple mRNAs and miRNAs for predicting chemoresistance COAD.
M, Mokhtarzadeh A, Baradaran B. Colon cancer therapy by focusing on colon cancer stem cells and their tumor microenvironment. J Cell Physiol. 2020;235:4153-66. DOI: 10.1002/jcp.29337
Azwar S, Seow HF, Abdullah M, Faisal Jabar M, Mohtarrudin N. Recent updates on mechanisms of resistance to 5-fluorouracil and reversal strategies in colon cancer treatment. Biology. 2021;10:854. DOI: 10.3390/biology10090854
Romani AM. Cisplatin in cancer treatment. Bio¬chem Pharmacol. 2022;206:115323. DOI: 10.1016/j. bcp.2022.115323
Chen L, Yang F, Chen S, Tai J. Mechanisms on che¬motherapy resistance of colorectal cancer stem cells and research progress of reverse transforma¬tion: A mini-review. Front Med. 2022;9:995882. DOI: 10.3389/fmed.2022.995882
Haider T, Pandey V, Banjare N, Gupta PN, Soni V. Drug resistance in cancer: mechanisms and tack¬ling strategies. Pharmacol Rep. 2020;72:1125-51. DOI: 10.1007/s43440-020-00138-7
Bukowski K, Kciuk M, Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci. 2020;21:3233. DOI: 10.3390/ijms21093233
Ashique S, Bhowmick M, Pal R, Khatoon H, Kumar P, Sharma H, et al. Multi drug resistance in colorec¬tal cancer-approaches to overcome, advancements and future success. Adv Cancer Biol: Metastasis. 2024:100114. DOI: 10.1016/j.adcanc2024.100114
Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Meh¬ryary F, Hachilif R, et al. The STRING database in 2023: protein-protein association networks and func¬tional enrichment analyses for any sequenced ge¬nome of interest. Nucleic Acids Res. 2023;51:D638– D46. DOI: 10.1093/nar/gkac1000
Li T, Fu J, Zeng Z, Cohen D, Li J, Chen Q, et al. TIMER2. 0 for analysis of tumor-infiltrating im¬mune cells. Nucleic Acids Res. 2020;48:W509-W14. DOI: 10.1093/nar/gkaa407
Huang HY, Lin YC, Cui S, Huang Y, Tang Y, Xu J, et al. miRTarBase update 2022: an informative resource for experimentally validated miRNA-target interactions. Nucleic Acids Res. 2022;50:D222–D30. DOI: 10.1093/ nar/gkab1079
Kang J, Tang Q, He J, Li L, Yang N, Yu S, et al. RNAInter v4. 0: RNA interactome repository with redefined confidence scoring system and improved accessibility. Nucleic Acids Res. 2022;50:D326-D32. DOI: 10.1093/nar/gkab997
Dong Q, Li F, Xu Y, Xiao J, Xu Y, Shang D, et al. RNAactDrug: a comprehensive database of RNAs as¬sociated with drug sensitivity from multi-omics data. Brief Bioinform. 2020;21:2167-74. DOI: 10.1093/bib/ bbz142
Ye J, Wu J, Liu B. Therapeutic strategies of dual-tar¬get small molecules to overcome drug resistance in cancer therapy. Biochim Biophys Acta Rev Cancer. 2023;1878:188866. DOI:1 0.1016/j.bbcan.2023.188866
Chen T, Xiao Z, Liu X, Wang T, Wang Y, Ye F, et al. Natural products for combating multidrug resis¬tance in cancer. Pharmacol Res. 2024;202:107099. DOI: 10.1016/j.phrs.2024.107099
Ye SB, Cheng YK, Deng R, Deng Y, Li P, Zhang L, et al. The Predictive Value of Estrogen Receptor 1 on Adju-vant Chemotherapy in Locally Advanced Colorectal Cancer: A Retrospective Analysis With Independent Validation and Its Potential Mechanism. Front On¬col. 2020;10:214. DOI: 10.3389/fonc.2020.00214
Li X, Wu Y, Tian T. TGF-β signaling in metastatic col¬orectal cancer (mCRC): from underlying mechanism to potential applications in clinical development Int J Mol Sci. 2022;23:14436. DOI: 10.3390/ijms232214436
Pabla B, Bissonnette M, Konda VJ. Colon cancer and the epidermal growth factor receptor: Current treat¬ment paradigms, the importance of diet, and the role of chemoprevention. World J Clin Oncol. 2015;6:133. DOI: 10.5306/wjco.v6.i5.133
Aldinucci D, Borghese C, Casagrande N. The CCL5/CCR5 axis in cancer progression. Cancers. 2020;12:1765. DOI: 10.3390/cancers12071765
Schlechter BL, Stebbing J. CCR5 and CCL5 in met¬astatic colorectal cancer. J immunotherap cancer. 2024;12. DOI: 10.1136/jitc-2023-008722
Battaglin F, Baca Y, Millstein J, Yang Y, Xiu J, Arai H, et al. Ccr5 and Ccl5 gene expression in colorectal cancer: comprehensive profiling and clinical value. J Immunother Cancer. 2024;12. DOI: 10.1136/jitc- 2023-007939
Erin N, Grahovac J, Brozovic A, Efferth T. Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance. Drug Resist Updat. 2020;53:100715. DOI: 10.1016/j.drup.2020.100715
Feng B, Wu J, Shen B, Jiang F, Feng J. Cancer-asso¬ciated fibroblasts and resistance to anticancer ther¬apies: status, mechanisms, and countermeasures. Cancer Cell Int. 2022;22:166. DOI: 10.1186/s12935- 022-02599-7
Bu L, Baba H, Yasuda T, Uchihara T, Ishimoto T. Functional diversity of cancer‐associated fibro¬blasts in modulating drug resistance. Cancer Sci. 2020;111:3468-77. DOI: 10.1111/cas.14578
Yang X, Lou Y, Wang M, Liu C, Liu Y, Huang W. miR 675 promotes colorectal cancer cell growth depen¬dent on tumor suppressor DMTF1. Mol Med Rep. 2019;19:1481–90. DOI: 10.3892/mmr.2018.9780
Wang YH, Chang SC, Ansar M, Hung CS, Lin RK. Eps15 homology domain-containing protein 3 hy-permethylation as a prognostic and predictive mark¬er for colorectal cancer. Biomedicines. 2021;9:453. DOI: 10.3390/biomedicines9050453
Grigoreva T, Sagaidak A, Novikova D, Tribulovich V. New Insights into Chemoresistance Mediat¬ed by Mdm2 Inhibitors: The Benefits of Targeted Therapy over Common Cytostatics. Biomedicines. 2024;12:547. DOI: 10.3390/biomedicines12030547
Elshazli RM, Toraih EA, Elgaml A, Kandil E, Faw¬zy MS. Genetic polymorphisms of TP53 (rs1042522) and MDM2 (rs2279744) and colorectal cancer risk: An updated meta-analysis based on 59 case-con¬trol studies. Gene. 2020;734:144391. DOI: 10.1016/j. gene.2020.144391
Kim KM, Ahn AR, Park HS, Jang KY, Moon WS, Kang MJ, et al. Clinical significance of p53 protein expression and TP53 variation status in colorectal cancer. BMC cancer. 2022;22:940. DOI: 10.1186/ s12885-022-10039-y
Ring BZ, Murali R, Soslow RA, Bowtell DDL, Fere¬day S, deFazio A, et al. Transducin-Like Enhancer of Split 3 (TLE3) Expression Is Associated with Taxane Sensitivity in Nonserous Ovarian Carcinoma in a Three-Cohort Study. Cancer Epidemiol Biomarkers Prev. 2018;27:680–8. DOI: 10.1158/1055-9965.EPI- 17-1101
Wei SC, Tsao PN, Weng MT, Cao Z, Wong JM. Flt- 1 in colorectal cancer cells is required for the tumor invasive effect of placental growth factor through a p38-MMP9 pathway. J Biomed Sci. 2013;20:1-12. DOI: 10.1186/1423-0127-20-39
Li P, Chen W, Wang Y, Fu X, Wen K, Qian J, et al. Effects of ephrinB2 gene siRNA on the biological be¬havior of human colorectal cancer cells. Oncol Rep. 2015;33:758-66. DOI: 10.3892/or.2014.3633
Azwar S, Seow HF, Abdullah M, Faisal Jabar M, Mohtarrudin N. Recent updates on mechanisms of resistance to 5-fluorouracil and reversal strategies in colon cancer treatment. Biology. 2021;10:854. DOI: 10.3390/biology10090854
Romani AM. Cisplatin in cancer treatment. Bio¬chem Pharmacol. 2022;206:115323. DOI: 10.1016/j. bcp.2022.115323
Chen L, Yang F, Chen S, Tai J. Mechanisms on che¬motherapy resistance of colorectal cancer stem cells and research progress of reverse transforma¬tion: A mini-review. Front Med. 2022;9:995882. DOI: 10.3389/fmed.2022.995882
Haider T, Pandey V, Banjare N, Gupta PN, Soni V. Drug resistance in cancer: mechanisms and tack¬ling strategies. Pharmacol Rep. 2020;72:1125-51. DOI: 10.1007/s43440-020-00138-7
Bukowski K, Kciuk M, Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci. 2020;21:3233. DOI: 10.3390/ijms21093233
Ashique S, Bhowmick M, Pal R, Khatoon H, Kumar P, Sharma H, et al. Multi drug resistance in colorec¬tal cancer-approaches to overcome, advancements and future success. Adv Cancer Biol: Metastasis. 2024:100114. DOI: 10.1016/j.adcanc2024.100114
Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Meh¬ryary F, Hachilif R, et al. The STRING database in 2023: protein-protein association networks and func¬tional enrichment analyses for any sequenced ge¬nome of interest. Nucleic Acids Res. 2023;51:D638– D46. DOI: 10.1093/nar/gkac1000
Li T, Fu J, Zeng Z, Cohen D, Li J, Chen Q, et al. TIMER2. 0 for analysis of tumor-infiltrating im¬mune cells. Nucleic Acids Res. 2020;48:W509-W14. DOI: 10.1093/nar/gkaa407
Huang HY, Lin YC, Cui S, Huang Y, Tang Y, Xu J, et al. miRTarBase update 2022: an informative resource for experimentally validated miRNA-target interactions. Nucleic Acids Res. 2022;50:D222–D30. DOI: 10.1093/ nar/gkab1079
Kang J, Tang Q, He J, Li L, Yang N, Yu S, et al. RNAInter v4. 0: RNA interactome repository with redefined confidence scoring system and improved accessibility. Nucleic Acids Res. 2022;50:D326-D32. DOI: 10.1093/nar/gkab997
Dong Q, Li F, Xu Y, Xiao J, Xu Y, Shang D, et al. RNAactDrug: a comprehensive database of RNAs as¬sociated with drug sensitivity from multi-omics data. Brief Bioinform. 2020;21:2167-74. DOI: 10.1093/bib/ bbz142
Ye J, Wu J, Liu B. Therapeutic strategies of dual-tar¬get small molecules to overcome drug resistance in cancer therapy. Biochim Biophys Acta Rev Cancer. 2023;1878:188866. DOI:1 0.1016/j.bbcan.2023.188866
Chen T, Xiao Z, Liu X, Wang T, Wang Y, Ye F, et al. Natural products for combating multidrug resis¬tance in cancer. Pharmacol Res. 2024;202:107099. DOI: 10.1016/j.phrs.2024.107099
Ye SB, Cheng YK, Deng R, Deng Y, Li P, Zhang L, et al. The Predictive Value of Estrogen Receptor 1 on Adju-vant Chemotherapy in Locally Advanced Colorectal Cancer: A Retrospective Analysis With Independent Validation and Its Potential Mechanism. Front On¬col. 2020;10:214. DOI: 10.3389/fonc.2020.00214
Li X, Wu Y, Tian T. TGF-β signaling in metastatic col¬orectal cancer (mCRC): from underlying mechanism to potential applications in clinical development Int J Mol Sci. 2022;23:14436. DOI: 10.3390/ijms232214436
Pabla B, Bissonnette M, Konda VJ. Colon cancer and the epidermal growth factor receptor: Current treat¬ment paradigms, the importance of diet, and the role of chemoprevention. World J Clin Oncol. 2015;6:133. DOI: 10.5306/wjco.v6.i5.133
Aldinucci D, Borghese C, Casagrande N. The CCL5/CCR5 axis in cancer progression. Cancers. 2020;12:1765. DOI: 10.3390/cancers12071765
Schlechter BL, Stebbing J. CCR5 and CCL5 in met¬astatic colorectal cancer. J immunotherap cancer. 2024;12. DOI: 10.1136/jitc-2023-008722
Battaglin F, Baca Y, Millstein J, Yang Y, Xiu J, Arai H, et al. Ccr5 and Ccl5 gene expression in colorectal cancer: comprehensive profiling and clinical value. J Immunother Cancer. 2024;12. DOI: 10.1136/jitc- 2023-007939
Erin N, Grahovac J, Brozovic A, Efferth T. Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance. Drug Resist Updat. 2020;53:100715. DOI: 10.1016/j.drup.2020.100715
Feng B, Wu J, Shen B, Jiang F, Feng J. Cancer-asso¬ciated fibroblasts and resistance to anticancer ther¬apies: status, mechanisms, and countermeasures. Cancer Cell Int. 2022;22:166. DOI: 10.1186/s12935- 022-02599-7
Bu L, Baba H, Yasuda T, Uchihara T, Ishimoto T. Functional diversity of cancer‐associated fibro¬blasts in modulating drug resistance. Cancer Sci. 2020;111:3468-77. DOI: 10.1111/cas.14578
Yang X, Lou Y, Wang M, Liu C, Liu Y, Huang W. miR 675 promotes colorectal cancer cell growth depen¬dent on tumor suppressor DMTF1. Mol Med Rep. 2019;19:1481–90. DOI: 10.3892/mmr.2018.9780
Wang YH, Chang SC, Ansar M, Hung CS, Lin RK. Eps15 homology domain-containing protein 3 hy-permethylation as a prognostic and predictive mark¬er for colorectal cancer. Biomedicines. 2021;9:453. DOI: 10.3390/biomedicines9050453
Grigoreva T, Sagaidak A, Novikova D, Tribulovich V. New Insights into Chemoresistance Mediat¬ed by Mdm2 Inhibitors: The Benefits of Targeted Therapy over Common Cytostatics. Biomedicines. 2024;12:547. DOI: 10.3390/biomedicines12030547
Elshazli RM, Toraih EA, Elgaml A, Kandil E, Faw¬zy MS. Genetic polymorphisms of TP53 (rs1042522) and MDM2 (rs2279744) and colorectal cancer risk: An updated meta-analysis based on 59 case-con¬trol studies. Gene. 2020;734:144391. DOI: 10.1016/j. gene.2020.144391
Kim KM, Ahn AR, Park HS, Jang KY, Moon WS, Kang MJ, et al. Clinical significance of p53 protein expression and TP53 variation status in colorectal cancer. BMC cancer. 2022;22:940. DOI: 10.1186/ s12885-022-10039-y
Ring BZ, Murali R, Soslow RA, Bowtell DDL, Fere¬day S, deFazio A, et al. Transducin-Like Enhancer of Split 3 (TLE3) Expression Is Associated with Taxane Sensitivity in Nonserous Ovarian Carcinoma in a Three-Cohort Study. Cancer Epidemiol Biomarkers Prev. 2018;27:680–8. DOI: 10.1158/1055-9965.EPI- 17-1101
Wei SC, Tsao PN, Weng MT, Cao Z, Wong JM. Flt- 1 in colorectal cancer cells is required for the tumor invasive effect of placental growth factor through a p38-MMP9 pathway. J Biomed Sci. 2013;20:1-12. DOI: 10.1186/1423-0127-20-39
Li P, Chen W, Wang Y, Fu X, Wen K, Qian J, et al. Effects of ephrinB2 gene siRNA on the biological be¬havior of human colorectal cancer cells. Oncol Rep. 2015;33:758-66. DOI: 10.3892/or.2014.3633
| Files | ||
| Issue | Vol 16 No 1 (2024) | |
| Section | Original Articles | |
| DOI | https://doi.org/10.18502/bccr.v16i1.18755 | |
| Keywords | ||
| 5-Fluorouracil Cisplatin Colon adenocarcinoma Drug resistance HCT8 cell line | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Jahanafrooz Z. Bioinformatics screening of therapeutic targets in chemoresistance human colon cancer HCT8 cell line. Basic Clin Cancer Res. 2025;16(1):23-32.
