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K. Kerkentzes
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-089 - MicroRNA miR-615-3p and let-7b Targets Multiple Key Pathways Overexpressed in Lung Adenocarcinoma (ID 2236)
09:30 - 09:30 | Author(s): K. Kerkentzes
- Abstract
Background:
Lung adenocarcinoma gene expression is highly aberrant and heterogeneous and not due to mutations in all these protein-coding genes. Epigenetic regulation by microRNAs has been shown to explain some of this dysregulation. We aimed at identifying whether few microRNAs could explain multiple overexpressed genes in key pathways of lung adenocarcinoma.
Methods:
Publicly available gene expression profiling data from three different publications were included in this in silico analysis. In the lung adenocarcinomas (n=139/49/45) and normal lung tissue (n=17/9/65) among the common 8543 genes (based on the EntrezID), the differentially expressed and diagnostic genes were investigated. The genes with q-value under 0.01 and with concordant regulation among all three datasets were regarded as significantly differentially expressed. Diagnostic genes were identified through the performance of each differentially expressed gene as a classifier. Finally, the miRNAs with highly probable predicted (PCT>0.9 in TargetScan), miRNA targeting interactions (MTI) and/or with experimentally validated MTIs were assessed, the number of gene targets in the down- or up-regulated genes measured for each miRNA and an enrichment analysis was performed.
Results:
The common overexpressed and down-regulated genes among the three datasets were 534 and 638 respectively. Among the diagnostic genes with AUC over 0.8 were the known genes encoding recently discovered diagnostic proteins but also new unknown genes. Among the pathways in KEGG, genes of the Cell Cycle, Carbon-pool by Folate and Base Excision and Mismatch Repair were significantly overexpressed. Importantly, we identified few microRNAs (q‹ 0.01) that could target most of these genes and that are all previously shown to be down-regulated and validated in lung and/or other cancer. Among the top microRNA were the following; Mir-615-3p targets 86 highly over-expressed genes in all three datasets. This microRNA was recently shown to act as a tumor suppressor through inhibition of the AKT2 in pancreatic cancer cell lines. Let-7b targets 83 highly over-expressed genes in all three datasets. Let-7b is controlling genomic balance and is down-regulated in aggressive breast cancer and significantly reduced in serum is correlated to poor survival in resectable NSCLC. Mir-16 targets 75 of the up-regulated genes in adenocarcinoma and was verified down-regulated in NSCLC versus adjacent normal lung tissue. Mir-193b targets 65 genes and was identified as a tumor suppressor in NSCLC and hepatocellular carcinoma. Mir-320a targets 50 genes and was identified as a crucial miRNA regulating glycolysis and was verified down-regulated in NSCLC. Mir-34a targets 46 of the overexpressed genes and is a crucial miRNA down-regulated in lung cancer and already proposed as a treatment with cisplatin.
Conclusion:
By combined in-silico analysis of three large datasets on adenocarcinoma versus normal adjacent lung tissue we detected novel candidate diagnostic genes and important pathways that recapitulate the phenotype of this cancer. Importantly, we found microRNAs that could target and thus explain a large portion of the pathway dysregulation. One of these identified microRNAs, miR-34a, has already demonstrated a therapeutic potential in lung cancer.
