Abstract
Schwann cells were identified in the tumor surrounding area prior to initiate the invasion process underlying connective tissue. These cells promote cancer invasion through direct contact, while paracrine signaling and matrix remodeling are not sufficient to proceed. Considering the intertwined structure of signaling, regulatory, and metabolic processes within a cell, we employed a genome-scale biomolecular network. Accordingly, a meta-analysis of Schwann cells associated transcriptomic datasets was performed, and the core information on differentially expressed genes (DEGs) was obtained by statistical analyses. Gene set over-representation analyses was performed on core DEGs to identify significantly functional and pathway enrichment analysis between Schwann cells and, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). DEGs were further integrated with genome-scale human biomolecular networks. miRNAs were proposed by the reconstruction of a transcriptional and post-transcriptional regulatory network. Moreover, microarray-based transcriptome profiling was performed, and the prognostic power of selected dedifferentiated Schwann cell biomolecules was predicted. We observed that pathways associated with Schwann cells dedifferentiation was overexpressed in lung cancer samples. However, genes associated with Schwann cells migration inhibition system were downregulated. Besides, miRNA targeting those pathways were also deregulated. In this study, we report valuable data for further experimental and clinical analysis, because the proposed biomolecules have significant potential as systems biomarkers for screening or for therapeutic purposes in perineural invasion of lung cancer.
Highlights
Peripheral nervous system plays an important role in neoplastic invasion
Paracrine signaling has been implicated in perineural invasion, with factors secreted by nerves, including glial cell line derived neurotrophic factor (GDNF), increasing the invasion of tumor cells along the nerves [5, 6]
The results revealed that downregulated consistent differentially expressed genes (DEGs) indicated the genes that were associated with the top four pathways: “Complement and coagulation cascades”, “Vascular smooth muscle contraction”, “Cell adhesion molecules (CAMs)” and, “Neuroactive ligand-receptor interaction”
Summary
Peripheral nervous system plays an important role in neoplastic invasion. The glial cells present in this system, Schwann cells, have been associated with the process known as perineural invasion. The main questions are how the neoplastic cells interact with the cells of the nervous system and how they acquire mobile and invasive characteristics from these interactions. Schwann cells become dedifferentiated, lose their capacity to myelinate and, promote neuronal orientation during repair [3]. This is accompanied by the reexpression of proteins lost during the myelinizing differentiation program, such as the glial fibrillary acidic protein (GFAP) and the neural cell adhesion molecule 1 (NCAM1) [1, 4]. Paracrine signaling has been implicated in perineural invasion, with factors secreted by nerves, including glial cell line derived neurotrophic factor (GDNF), increasing the invasion of tumor cells along the nerves [5, 6]
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