| Anticancer drug resistance is a common cause of cancer therapy failure,which is a complex process and its molecular mechanism needs to be further explored.However,identifying new therapeutic targets to overcome drug resistance is still one of the main challenges in drug research and development.We need a comprehensive understanding of the mechanism of drug resistance to further prevent and avoid drug resistance.However,there are few studies to systematically conduct in-depth analysis of drug resistance caused by abnormal gene transcription levels and transcription regulation disorders.This study focuses on a comprehensive analysis of complex transcriptome changes,including m RNA differences and long non-coding RNA,as well as the corresponding disorders of transcriptional regulation and competing endogenous networks.In this study,data of drug sensitivity,transcriptional and epigenetic data of cell lines were obtained from GDSC and CCLE,respectively.Combined with bioinformatics analysis methods,the molecular targets of a total of 208 anticancer drugs or small analytical compounds related to drug resistance were analyzed and explored on pan-drug and pan-cancer.The specific results are as follows:1.The m RNA expression spectrum data of the cell lines treated by 208 drugs were obtained from the CCLE database,and the IC50 values of the cell lines treated by anticancer drugs provided by GDSC were divided into drug-resistant(DR)group and drug-sensitive(DS)group.The differentially expressed genes in DS and DR group were obtained by edge R software package.The thresholds for screening differentially expressed genes were Benjamini-Hochberg(BH)<0.05(P value was corrected by multiple test)and |log2(Fold Change)|>1.5.The results showed that among the cross-drug types,8～1282 genes were differentially expressed in DR group.According to the integrated data of mutil-drugs,it was found that 428 m RNAs were differentially expressed in 40 or more drug types,such as ABCB1,CYP1A1,CYP3A5,ERBB2,ERBB3 and so on.The KEGG pathway enrichment analysis of the differential genes of the above 208 drugs showed that the differential genes were mainly involved in the activation of cell attachment and adhesion and activation of various signal transduction pathways,which led to the process of drug resistance in cancer.2.The analysis of the promoter methylation of the differential expression m RNAs of the above 10 drugs showed that the methylation of the upstream promoter site decreased in most of the m RNAs in each drug,but the hypermethylation of the genes was relatively few.We found methylation disorders of some key genes in many drugs such as GRB7,CLDN3,and ST8SIA4.At the same time,in order to further explore the effect of transcriptional regulation on transcriptional factors and target genes,in our analysis of the interaction between transcriptional factors and target genes in DR group,we found that the interaction between transcription factors and target genes in DR group was significantly higher than that in SD group,indicating the disorder of transcriptional regulation of drug-resistant cell lines.Combined with the hub transcription factors in DR group and previous methylation analysis,we found that the methylation of transcription factor SOX2 was decreased and the gene expression was upregulated in many drugs,and the downstream enhanced regulation of multiple target genes were related to cell proliferation and adhesion,and the samples with highly expressed SOX2 compared to the low have a poor prognosis,indicating that transcription factor SOX2 has potential to be a target for drug resistance therapy.In addition,the production of DNA methylation directly interfered with the binding of the specific transcription factor with its recognized promoter.After integrated analysis,we found that ABCB1,EGFR and PTGS2 regulated by transcription factor NFKB1 downstream compared with DS group showed hypomethylation,and its transcription was significantly up-regulated compared with DS group,and the interaction between its transcription factor NFKB1 and its promoter was also significantly increased in DR group.Therefore,this study speculates that the decrease of the methylation of these three genes leads to the enhancement of the binding of transcription factor NFKB1 to it,which further promotes the enhancement of expression,which leads to the occurrence and development of drug resistance,and the samples with highly expression of NFKB1 EGFR and PTGS2 have relatively poor prognosis in TCGA,which provides potential transcription factors and epigenetic modification targets for the treatment of drug resistance.3.In this reasearch,according to the ce RNA theory,the differentially expressed lnc RNA in DR group and DS group were obtained and combined with differentially expressed m RNA,as potential nodes in the ce RNA regulatory network related to drug resistance.According to the common micro RNA in the network,the interaction regulatory network was constructed,and the up-and down-regulated and significantly co-expressed lnc RNA-m RNA pairs were selected to construct ce RNA regulatory network.The results of gene functional enrichment analysis showed that the ce RNA regulatory network related to drug resistance was closely related to cancer and drug resistance of cancer.Then through the evaluation of lnc RNA nodes with higher network connectivity,it is found that DLX6-AS1 LINC00483 and LINC00943 as the hub lnc RNA participate in the regulatory network of anticancer drug resistance,such as Docetaxel Midostaurin and cisplatin,respectively.And the expression of DLX6-AS1 and LINC000943 in TCGA is closely related to the prognosis of cancer patients,revealing the potential important role of lnc RNA in the regulation mechanism of drug resistance-related ce RNA.Conclusion: In this paper,the differences of genes related to drug resistance were analyzed by bioinformatics methods,and it was found that many genes were disordered in many kinds of cancers.The enrichment analysis of differential genes obtained in this paper showed that they were mainly involved in cell junction and adhesion and the activation of various signal transduction pathways.At the same time,this paper found and revealed the effects of DNA methylation dysfunction of some key genes,such as GRB7,CLDN3,ST8SIA4,SOX2,NFKB1,ABCB1,EGFR and PTGS2 and the disorder of interaction between transcription factors and target genes on drug resistance of cell lines.In addition,this study also analyzed the disorder of lnc RNA in drug-resistant cancer cell lines,and predicted the regulatory function of DLX6-AS1 LINC00483 and LINC00943 in drug resistance of cancer,so as to provide potential methods for clinical treatment.The purpose of this study is to find the potential targets of drug resistance of cancer by pan-cancer and pan-drug method,and to find,reverse and stop the occurrence and development of drug resistance by detecting or regulating these potential targets,which also provides a useful research scheme for the study of drug resistance of other drugs. |
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