Varied clinical significance of ATP-binding cassette C sub-family members for lung adenocarcinoma

Abstract

Lung adenocarcinoma (LUAD) is a lethal malignancy worldwide and a major public health concern. We explored the potential clinical significance for LUAD of ATP-binding cassette (ABC), sub-family C, consisting of ABCC1-6, 8-12, and cystic fibrosis transmembrane conductance regulator (CFTR).Five hundred LUAD patients from The Cancer Genome Atlas database were used for analysis, including differential expression and diagnostic and prognostic significance. Oncomine and MERAV databases were used to validate differential expression and diagnostic significance. A risk score model was constructed using prognosis-related ABCC members. Prognosis-related genes were further explored to correlate their expression with tumor stage progression. Interaction networks, including biological processes and metabolic pathways, were constructed using Cytoscape software and STRING website.ABCC1-3 consistently showed high expression in tumor tissues (all P ≤ 0.05). Most datasets indicated that ABCC5, 10, and 11 were highly expressed in tumor tissues whereas ABCC6, 9, and CFTR were highly expressed in nontumor tissues (all P ≤ 0.05). Diagnostic significance of ABCC3 and ABCC5 was consistently assessed and validated in three datasets (all area under the curve > 0.700) whereas ABCC6, 8, 10, 11, and CFTR were assessed in The Cancer Genome Atlas dataset and validated in one dataset (all area under the curve > 0.700). Prognostic analysis indicated that ABCC2, 6, and 8 mRNA expression was associated with survival of LUAD (all adjusted P ≤ .037). The risk score model constructed using ABCC2, 6, and 8 suggested prognostic significance for survival predictions. ABCC2 expression was associated with tumor stage, whereas ABCC6 and 8 were not. Interaction networks indicated that they were involved in establishment of localization, ion transport, plasma membrane, apical plasma membrane, adenylyl nucleotide binding, ABC transporters, ABC transporter disorders, ABC-family-protein-mediated transport, and bile secretion.Differentially expressed ABCC2 and ABCC5 might be diagnostic whereas ABCC2, 6, and 8 may be prognostic biomarkers for LUAD, possibly through ABC-family-mediated transporter disorders.

Figure 1

Expression of ABCC subfamily in lung tumor and normal lung tissues. A–L: expression of ABCC1–6, cystic fibrosis transmembrane conductance regulator, and ABCC8–12 in lung tumor and normal lung tissues, respectively. ABCC = ATP-binding cassette C.

Figure 2

The mRNA expression of ABCC subfamily in lung adenocarcinoma and nontumor tissues in The Cancer Genome Atlas dataset. A–L: expression of ABCC1–6, cystic fibrosis transmembrane conductance regulator, and ABCC8–12 in lung adenocarcinoma and non-tumor tissues, respectively. ABCC = ATP-binding cassette C.

Figure 3

Diagnostic ROC curves of ABCC subfamily in lung adenocarcinoma and nontumor tissues in The Cancer Genome Atlas dataset. A–L: diagnostic ROC curves of ABCC1–6, cystic fibrosis transmembrane conductance regulator, and ABCC8–12 in lung adenocarcinoma and nontumor tissues, respectively. ABCC = ATP-binding cassette C, ROC = receiver operating characteristic.

Figure 4

The mRNA expression and diagnostic ROC curves of ABCC subfamily in lung adenocarcinoma and nontumor tissues in Su, Garber, Selamat, and Beer datasets. A–H: mRNA expression of ABCC3, 5, 6, CFTR, and ABCC8–11, respectively; I–P: diagnostic ROC curves of ABCC3, 5, 6, CFTR, and ABCC8–11, respectively. ABCC = ATP-binding cassette C, CFTR = cystic fibrosis transmembrane conductance regulator, ROC = receiver operating characteristic.

Figure 5

Kaplan-Meier plots of ABCC subfamily in TCGA dataset. A–L: Kaplan-Meier plots of ABCC1–6, cystic fibrosis transmembrane conductance regulator, and ABCC8–12 in TCGA dataset, respectively. ABCC = ATP-binding cassette C, TCGA = The Cancer Genome Atlas.

Figure 6

Joint-effect analysis of ABCC2, 6, and 8 in TCGA dataset. A–D: joint-effect analysis of ABCC2 and 6; ABCC2 and 8; ABCC6 and 8; ABCC2, 6, and 8 in TCGA dataset, respectively. ABCC = ATP-binding cassette C, TCGA = The Cancer Genome Atlas.

Figure 7

Risk score model constructed using ABCC2, 6, and 8 in The Cancer Genome Atlas dataset. A: risk score model, including risk score ranking, patients survival, and ABCC2, 6, 8 expressions; B: Kaplan-Meier plot of risk score model; C: time-dependent receiver operating characteristic curves of risk score model in 1 to 5 years. ABCC = ATP-binding cassette C.

Figure 8

Scatter plots of ABCC expressions with tumor stage and ABCC with metabolic pathways. A–C: scatter plots of ABCC2, 6, and 8 expression with tumor stage; D: interaction network between ABCC members and metabolic pathways. ABCC = ATP-binding cassette C.

Figure 9

Coexpression matrix and interaction networks among ABCC members. A: coexpression matrix among ABCC members; B: gene–gene interaction network among ABCC members; D: protein–protein interaction network among ABCC members. ABCC = ATP-binding cassette C.

Figure 10

Biological processes network ATP-binding cassette C members are involved in.

Figure 11

Cellular components network ATP-binding cassette C members are involved in.

Figure 12

Molecular functions network ATP-binding cassette C members are involved in.

Figure 13

The mRNA expression and diagnostic ROC curves of ABCC subfamily in lung adenocarcinoma and nontumor tissues in Stearman, Hou, Su, and Landi datasets. A–H: mRNA expression of ABCC3, 5, 6, CFTR and ABCC8–11, respectively; I–P: diagnostic ROC curves of ABCC3, 5, 6, CFTR and ABCC8–11, respectively. ABCC = ATP-binding cassette C, CFTR = cystic fibrosis transmembrane conductance regulator, ROC = receiver operating characteristic.