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Analysis of RAGE Proteome and Interactome in Lung Adenocarcinoma Using PANTHER and STRING Databases
1School of Nursing and Health Studies, 5452University of Miami, Coral Gables, FL, USA.
Abstract:
Adenocarcinoma accounts for about 40% of all lung cancers. Histological studies indicate a loss of expression of the Receptor for Advanced Glycation End-products (RAGE) in lung adenocarcinoma cells compared to neighboring non-malignant tissue. Gene silencing of RAGE in human lung adenocarcinoma cells was performed and then cells were subjected to LC-MS/MS (n = 3, FDR < 1%). Differentially expressed proteins were analyzed using the PANTHER Classification System and STRING Interactome, identifying functions and protein-protein interaction networks. We observed expression of dominant-negative (DN-) RAGE, an isoform lacking the critical intracellular signaling tail observed in the full length (FL-) RAGE. Proteomic analysis suggests DN-RAGE likely plays a crucial role in cell polarity, metastases, and in cell-cell or cell-matrix complexes through focal adhesion or adherens junction formation. DN-RAGE may also regulate the expression of FL-RAGE and may provide a "switch" that could transition from a pro-inflammatory to a migratory cell as vimentin expression increased along with a reduction in cell polarity proteins. STRING interactome analysis identified seven protein-protein interaction networks involved in the regulation of gene expression, cell organization, cytoskeletal changes, sub-membrane plaque formation, as well as cytokinesis, cell shape, and motility. Suggesting expression of DN-RAGE may contribute to metastases and the development of advanced cancer.
Insights
The study reveals that a variant of the Receptor for Advanced Glycation End-products (RAGE), known as dominant-negative RAGE (DN-RAGE), may drive lung adenocarcinoma metastasis. This DN-RAGE isoform appears to promote cell migration and advanced cancer development.
Area of Science:
- Oncology
- Molecular Biology
- Proteomics
Background:
- Adenocarcinoma represents approximately 40% of all lung cancers.
- Reduced expression of the Receptor for Advanced Glycation End-products (RAGE) is observed in lung adenocarcinoma cells compared to normal tissue.
Purpose of the Study:
- To investigate the role of RAGE, specifically its dominant-negative isoform (DN-RAGE), in lung adenocarcinoma progression.
- To identify protein interaction networks associated with DN-RAGE expression.
Main Methods:
- Gene silencing of RAGE in human lung adenocarcinoma cells.
- Proteomic analysis using Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS).
- Bioinformatic analysis using PANTHER Classification System and STRING Interactome.
Main Results:
- Observed expression of DN-RAGE, an isoform lacking the intracellular signaling tail of full-length RAGE (FL-RAGE).
- Proteomic analysis suggests DN-RAGE influences cell polarity, metastasis, and cell-matrix interactions via focal adhesion and adherens junctions.
- DN-RAGE may regulate FL-RAGE expression, potentially switching cells from a pro-inflammatory to a migratory state, evidenced by increased vimentin and decreased cell polarity proteins.
- Seven protein-protein interaction networks were identified, implicating DN-RAGE in gene regulation, cell organization, cytoskeleton dynamics, and cell motility.
Conclusions:
- DN-RAGE expression is linked to critical cellular processes involved in cancer metastasis and progression.
- DN-RAGE may act as a switch, promoting a migratory phenotype in lung adenocarcinoma cells.
- Understanding DN-RAGE's role could offer new therapeutic targets for advanced lung adenocarcinoma.
