Genome-wide RNA-sequencing dataset reveals the prognostic value and potential molecular mechanisms of lncRNA in non-homologous end joining pathway 1 in early stage Pancreatic Ductal Adenocarcinoma

Abstract

Objective: Our current study is to explore the prognostic value and molecular mechanisms underlying the role of lncRNA in non-homologous end joining pathway 1 (LINP1) in early stage pancreatic ductal adenocarcinoma (PDAC). Methods: Genome-wide RNA-seq datasets of 112 early stage PDAC patients were got from The Cancer Genome Atlas and analyzed using multiple online tools. Results: Overall survival in high LINP1 expression patients was shorter than those with low expression (high-LINP1 vs. low-LINP1=481 vs. 592 days, log-rank P=0.0432). The multivariate Cox proportional hazard regression model suggested that high-LINP1 patients had a markedly higher risk of death than low-LINP1 patients (adjusted P=0.004, hazard ratio=2.214, 95% confidence interval=1.283-3.820). Analysis of genome-wide co-expressed genes, screening of differentially expressed genes, and gene set enrichment analysis indicated that LINP1 may be involved in the regulation of cell proliferation-, cell adhesion- and cell cycle-related biological processes in PDAC. Six small-molecule compounds including STOCK1N-35874, fenofibrate, exisulind, NU-1025, vinburnine, and doxylamine were identified as potential LINP1-targeted drugs for the treatment of PDAC. Conclusions: Our study indicated that LINP1 may serve as a prognostic biomarker of early stage PDAC. Analysis of genome-wide datasets led to the elucidation of the underlying mechanisms and identified six potential targeted drugs for the treatment of early PDAC.

Keywords: The Cancer Genome Atlas; lncRNA in non-homologous end joining pathway 1; molecular mechanism; pancreatic ductal adenocarcinoma; prognosis.

Figure 1

Survival analysis of LINP1 expression levels in early stage pancreatic adenocarcinoma (PDAC). (A) Relationship between LINP1 expression and OS in patients with PDAC. (B) Kaplan-Meier curve of the effect of LINP1 expression on OS in patients with PDAC. (C)Time dependent ROC curve of LINP1 for PDAC clinical outcome prediction.

Figure 2

Nomogram of the combination of LINP1 with clinical parameters for predicting the prognosis of patients with early PDAC.

Figure 3

Joint effects survival analysis of LINP1 and clinical parameters in PDAC OS. (A) Histological grade; (B) radiation therapy; (C) radical resection; (D) targeted molecular therapy.

Figure 4

Regulatory network of LINP1 co-expressed genes in PDAC tumor tissues.

Figure 5

Gene-gene interaction regulatory network of LINP1 co-expressed genes.

Figure 6

Protein-protein interaction regulatory network of LINP1 co-expressed genes.

Figure 7

Gene-gene interaction regulatory network of differentially expressed genes (DEGs) between high- and low-LINP1 expression groups.

Figure 8

Protein-protein interaction regulatory network of DEGs between high- and low-LINP1 expression groups.

Figure 9

CMap analysis results and small molecule compound structure. Chemical structure of Fenofibrate (A), Exisulind (B), NU-1025 (C), Vinburnine (D), Doxylamine (E), and CMap analysis results (F). Notes: The structure of STOCK1N-35874 is not available on the PubChem database.

Figure 10

GSEA results of the high LINP1 expression group in early stage PDAC using the c5 reference gene set (A-P). (A), PID PLK1 PATHWAY; (B), ALONSO METASTASIS UP; (C), ALONSO METASTASIS EMT UP; (E),KEGG CELL CYCLE; (F),REACTOME CELL CYCLE; (G), PID MTOM 4 PATHWAY; (H), KEGG PANCREATIC CANCER; (I), PID PI3KCI AKT PATHWAY; (J), REACTOME APOPTOTIC EXECUTION PHASE; (K), REACROME CELL CELL COMMUNICATION; (L), REACROME CELL JUNCTION ORGANIZTION; (M), REACROME P53 DEPENDENT G1 DNA DAMAGE RESPONE; (N), REACROME P53 INDEPENDENT G1 S DNA DAMAGE CHECKPOINT; (O), PID TGFBR PATHWAY; (P), REACTOME SIGNALING BY WNT.