Comprehensive characterization of a drug-resistance-related ceRNA network across 15 anti-cancer drug categories

Abstract

Cancer is still a major health problem around the world. The treatment failure of cancer has largely been attributed to drug resistance. Competitive endogenous RNAs (ceRNAs) are involved in various biological processes and thus influence the drug sensitivity of cancers. However, a comprehensive characterization of drug-sensitivity-related ceRNAs has not yet been performed. In the present study, we constructed 15 ceRNA networks across 15 anti-cancer drug categories, involving 217 long noncoding RNAs (lncRNAs), 158 microRNAs (miRNAs), and 1,389 protein coding genes (PCGs). We found that these ceRNAs were involved in hallmark processes such as "self-sufficiency in growth signals," "insensitivity to antigrowth signals," and so on. We then identified an intersection ceRNA network (ICN) across the 15 anti-cancer drug categories. We further identified interactions between genes in the ICN and clinically actionable genes (CAGs) by analyzing the co-expressions, protein-protein interactions, and transcription factor-target gene interactions. We found that certain genes in the ICN are correlated with CAGs. Finally, we found that genes in the ICN were aberrantly expressed in tumors, and some were associated with patient survival time and cancer stage.

Keywords: Pan-cancer; ceRNA network; drug resistance; lncRNA.

Graphical abstract

Figure 1

ceRNA networks of 15 anti-cancer drugs Circular pink nodes represent miRNAs; triangular purple nodes represent lncRNAs; square green nodes represent PCGs.

Figure 2

Similarities across the 15 ceRNA networks and hub nodes analysis (A) Correlation of lncRNAs across the 15 ceRNA networks. (B) Correlation of miRNAs across the 15 ceRNA networks. (C) Correlation of PCGs across the 15 ceRNA networks. (D) Average values of the Jaccard coefficients of lncRNAs, miRNAs, and protein coding genes (PCGs). (E) Distribution map of the number of drug types in the 15 ceRNA networks. (F) Hub analysis of the ceRNA networks across the 15 anti-cancer drug categories. Distribution of the hub genes across the pan-drug ceRNA networks is shown. Purple boxes represent lncRNAs and green boxes represent PCGs.

Figure 3

Relevance between ceRNAs across the 15 drug categories and cancer hallmark processes (A) p values of the hypergeometric test that evaluated the significance of overlap between 15 ceRNA networks and cancer-lncRNAs, miRNAs, and PCGs, respectively. (B) Jaccard coefficient matrix for PCGs in the pan-drug ceRNA networks and cancer hallmark processes.

Figure 4

Intersection ceRNA networks (ICNs) of different drugs Circular pink nodes represent miRNAs; triangular purple nodes represent lncRNAs; and square green nodes represent PCGs.

Figure 5

Correlation between drug sensitivity and genes in the ICN Yellow indicates a negative correlation; red indicates a positive correlation; and size reflects absolute Pearson’s correlation coefficient (p value). Color bars in the y axis indicate drugs and their category.

Figure 6

Correlation of transcriptional expression between genes in the ICN and clinically actionable genes (CAGs) Pearson’s correlation coefficients |R| > 0.3, p < 0.05; blue indicates a negative correlation; red indicates a positive correlation; color scale reflects Pearson’s correlation coefficient. The x axis (CAGs) is ordered by the number of positively correlated genes in the ICN minus the number of negatively correlated genes in the ICN. The y axis (genes in the ICN) is ordered by the total number of correlated CAGs. If the number of cancer types is less than five, the fill color of the cell is white. Bold boxes highlight the transcriptional factor-gene interactions of CAGs and genes in the ICN. × marks the protein-protein interactions (PPIs) of CAGs and genes in the ICN based on the experimental evidence from HPRD.

Figure 7

Clinical relevance of the ICN across 21 kinds of cancer. (A) Clinical relevance of the ICN across different cancer types. Pink boxes indicate genes that are differently expressed between the ICN and different cancer samples. Dark yellow and light yellow boxes represent the upregulation or downregulation of genes in later stages (fold change of transcriptional expression between stages III/IV and stages I/II larger than 1.5). Dark green and light green boxes indicate high and low expression in tumors associated with worse overall survival times (log-rank test FDR < 0.05), respectively. (B) Kaplan-Meier curves of multiple cancer types stratified by median expression level of E2F2 and ITGB8.