Abstract
Small-cell lung carcinoma (SCLC) and large-cell neuroendocrine lung carcinoma (LCNEC) are high-grade lung neuroendocrine tumors (NET). However, comparative protein expression within SCLC and LCNEC remains unclear. Here, protein expression profiles were obtained via mass spectrometry-based proteomic analysis. Weighted gene co-expression network analysis (WGCNA) identified co-expressed modules and hub genes. Of 34 identified modules, six were significant and selected for protein–protein interaction (PPI) network analysis and pathway enrichment. Within the six modules, the activation of cellular processes and complexes, such as alternative mRNA splicing, translation initiation, nucleosome remodeling and deacetylase (NuRD) complex, SWItch/Sucrose Non-Fermentable (SWI/SNF) superfamily-type complex, chromatin remodeling pathway, and mRNA metabolic processes, were significant to SCLC. Modules enriched in processes, including signal recognition particle (SRP)-dependent co-translational protein targeting to membrane, nuclear-transcribed mRNA catabolic process of nonsense-mediated decay (NMD), and cellular macromolecule catabolic process, were characteristically activated in LCNEC. Novel high-degree hub genes were identified for each module. Master and upstream regulators were predicted via causal network analysis. This study provides an understanding of the molecular differences in tumorigenesis and malignancy between SCLC and LCNEC and may help identify potential therapeutic targets.
Highlights
Small-cell lung carcinoma (SCLC) and large-cell neuroendocrine carcinoma (LCNEC) are classified into high-grade lung neuroendocrine tumors (NETs) [1]
The primary objectives of this study were to capture molecular insights into the tumorigenic difference between SCLC and LCNEC and to construct a gene coexpression network using Weighted gene co-expression network analysis (WGCNA) to identify and/or predict the candidate key network modules and Hub genes characteristically associated with the carcinogenesis of each cancer subtype
We applied WGCNA to clinical proteomic datasets, for the first time to the best of our knowledge, for exploring molecular networks associated with tumorigenesis that characterize SCLC and LCNEC
Summary
Small-cell lung carcinoma (SCLC) and large-cell neuroendocrine carcinoma (LCNEC) are classified into high-grade lung neuroendocrine tumors (NETs) [1]. SCLC cells typically have a round to fusiform morphology and grow in sheets and nests that frequently include necrotic areas These tumor cells have scant cytoplasm, fine chromatin granules, and are less than three times the diameter of small, resting lymphocytes [3, 4]. LCNECs show a typical neuroendocrine morphology, including organoid nesting, cellular palisading, or rosette-like structures as well as high mitotic rates They can manifest cytological features of non-small-cell carcinomas, such as large cells with abundant cytoplasm. From the clinical point of view, these two histological types present similar patient characteristics, including a greater incidence in men ( in those who are heavy smokers), diagnosis at an older age, and worse prognosis Because patients with these histological types are usually discovered only in the advanced stages of the disease, surgically treated patients are rare. Because only few studies have evaluated the effectiveness of chemotherapy to date, a standard chemotherapy regimen has not yet been established for LCNEC [6]
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