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. 2020 Feb 15;20:128-139.
doi: 10.1016/j.omtn.2020.01.038. Online ahead of print.

Inferences of Individual Drug Response-Related Long Non-coding RNAs Based on Integrating Multi-omics Data in Breast Cancer

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Free PMC article

Inferences of Individual Drug Response-Related Long Non-coding RNAs Based on Integrating Multi-omics Data in Breast Cancer

Hao Cui et al. Mol Ther Nucleic Acids. .
Free PMC article

Abstract

Differences in individual drug responses are obstacles in breast cancer (BRCA) treatment, so predicting responses would help to plan treatment strategies. The accumulation of cancer molecular profiling and drug response data provide opportunities and challenges to identify novel molecular signatures and mechanisms of tumor responsiveness to drugs in BRCA. This study evaluated drug responses with a multi-omics integrated system that depended on long non-coding RNAs (lncRNAs). We identified drug response-related lncRNAs (DRlncs) by combining expression data of lncRNA, microRNA, messenger RNA, methylation levels, somatic mutations, and the survival data of cancer patients treated with drugs. We constructed an integrated and computational multi-omics approach to identify DRlncs for diverse chemotherapeutic drugs in BRCA. Some DRlncs were identified with Adriamycin, Cytoxan, Tamoxifen, and all samples for BRCA patients. These DRlncs showed specific features regarding both expression and computational accuracies. The DRlnc-gene co-expression networks were constructed and analyzed. Key DRlncs, such as HOXA-AS2 (Ensembl: ENSG00000253552), in the drug Adriamycin were characterized. The experimental analysis also suggested that HOXA-AS2 (Ensembl: ENSG00000253552) was a key DRlnc in Adriamycin drug resistance in BRCA patients. Some DRlncs were associated with survival and some specific functions. A possible mechanism of DRlnc HOXA-AS2 (Ensembl: ENSG00000253552) in the Adriamycin drug response for BRCA resistance was inferred. In summary, this study provides a framework for lncRNA-based evaluation of clinical drug responses in BRCA. Understanding the underlying molecular mechanisms of drug responses will facilitate improved responses to chemotherapy and outcomes of BRCA treatment.

Keywords: breast cancer; drug response; long non-coding RNAs; multi-omics integration; prognosis.

Figures

Figure 1
Figure 1
Identification of Individual DRlncs Based on Multi-omics Data Integration for Multiple Drugs in BRCA Patients (A) The bar plot shows the number of DRlncs for multiple drugs in BRCA patients. (B) The point plot shows the DRlncs for Adriamycin. The larger circles represent more significant p values of DRlncs. The x and y axes represent DRlncs and the number of factors. (C) The point plot shows the DRlncs for Tamoxifen. (D) The pie charts show the percent of diverse number of factors for multiple drugs. (E) The heatmap shows common DRlncs. Dark and light green represent DRlncs, which were influenced by three or two factors for multiple drugs, respectively. (F) The radar chart shows the numbers of methylation sites, genes, and mutations of DRlnc AC008443 (Ensembl: ENSG00000233937).
Figure 2
Figure 2
Individual DRlncs Showed Specific Features for Diverse Drugs in BRCA Patients (A) The bar plot shows the number of upregulated and downregulated DRlncs for diverse drugs. (B–E) The density distribution curves show the distribution of scores of DRlncs for methylations (green), mutations (red), miRNAs (yellow), and genes (blue) with (B) Adriamycin, (C) Cytoxan, (D) Tamoxifen, and (E) all samples. (F) The density distribution curves show the distribution of the last scores of DRlncs for Adriamycin (green), Cytoxan (yellow), Tamoxifen (blue), and all samples (red). (G) The boxplots show the expressions of HOXA-AS2 (Ensembl: ENSG00000253552) and HNRNPA2B1 (Ensembl: ENSG00000122566) for Adriamycin-sensitive (green) and -resistant (red) BRCA patients. (H) The point plot shows the co-expression between HOXA-AS2 (Ensembl: ENSG00000253552) and HNRNPA2B1 (Ensembl: ENSG00000122566). (I) The heatmap shows the expressions of HOXA-AS2 (Ensembl: ENSG00000253552) and HNRNPA2B1 (Ensembl: ENSG00000122566). Red and blue represent high and low expression levels, respectively.
Figure 3
Figure 3
The DRlnc-Gene Co-expression Networks Related to Drug Responses in Breast Cancer (A) The bar plot shows the number of positive and negative correlated interactions for diverse drugs. (B) The co-expression DRlnc-gene network for all drugs, including Adriamycin, Cytoxan, Tamoxifen, and all samples. The yellow circle and green triangle represent DRlnc and genes, respectively. The red and blue edges represent positive and negative interactions between DRlnc and genes, respectively. The thickness of edges represents correlation levels between DRlnc and genes. (C) The plots show the degree of distribution of the total DRlnc-gene co-expression network. (D) The DRlnc-gene co-expression network for Adriamycin. (E) The heatmap shows the expression level of DRlnc AC073611 (Ensembl: ENSG00000257605) and its interacting genes, including CAPRIN1, UPF1 (Ensembl: ENSG00000005007), and CSTF2 (Ensembl: ENSG00000101811). (F–H) The DRlnc-gene co-expression network for (F) Cytoxan, (G) Tamoxifen, and (H) all samples.
Figure 4
Figure 4
Some DRlncs Were Associated with Survival of Breast Cancer Patients (A1-D1) The Kaplan-Meier curves for the overall survival of two DRlnc groups with high- and low-risk expressions. The difference between the two curves was evaluated by a two-sided log rank test. (A2-D2) The expression distribution of the DRlnc in each drug. (A3-D3) The patient survival status of the DRlnc for diverse drugs in BRCA patients.
Figure 5
Figure 5
The Functions and Mechanism of DRlncs for Diverse Drugs in BRCA Patients (A–D) Bar plots show the p values of Gene Ontology enrichment terms for DRlncs for Adriamycin (A), Cytoxan (B), Tamoxifen (C), and all samples (D). (E) The possible mechanism of DRlnc HOXA-AS2 (Ensembl: ENSG00000253552) in drug responses for BRCA patients.
Figure 6
Figure 6
HOXA-AS2 Promotes the Adriamycin Resistance of BRCA Cells (A) Quantitative real-time PCR was used to detect the expression of HOXA-AS2 in BRCA tissues from patients with or without Adriamycin-based neoadjuvant chemotherapy before surgery. The expression of HOXA-AS2 was examined by real-time PCR in normal or adriamycin-resistant (B) T47D and (C) MDA-MB-231 cells. (D) The efficiency of HOXA-AS2 (Ensembl: ENSG00000253552) knockdown by shRNAs was confirmed in BRCA cells. (E) With 5 mg/L Adriamycin treatment, colony formation assays were performed to analyze the proliferative ability of normal, Adriamycin-resistant, or HOXA-AS2 (Ensembl: ENSG00000253552)-knockdown Adriamycin-resistant BRCA cells.

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