Abstract
BackgroundIn our recent study, most non-small-lung cancer (NSCLC) tumor specimens harbored viral DNA but it was absent in non-neoplastic lung. However, their targets and roles in the tumor cells remain poorly understood. We analyzed gene expression microarrays to identify genes and pathways differentially altered between virus-infected and uninfected NSCLC tumors.MethodsGene expression microarrays of 30 primary and 9 metastatic NSCLC patients were preprocessed through a series of quality control analyses. Linear Models for Microarray Analysis and Gene Set Enrichment Analysis were used to assess differential expression.ResultsVarious genes and gene sets had significantly altered expressions between virus-infected and uninfected NSCLC tumors. Notably, 22 genes on the viral carcinogenesis pathway were significantly overexpressed in virus-infected primary tumors, along with three oncogenic gene sets. A total of 12 genes, as well as seven oncogenic and 133 immunologic gene sets, were differentially altered in squamous cell carcinomas, depending on the virus. In adenocarcinoma, 14 differentially expressed genes (DEGs) were identified, but no oncogenic and immunogenic gene sets were significantly altered. In bronchioloalveolar carcinoma, several genes were highly overexpressed in virus-infected specimens, but not statistically significant. Only five of 69 DEGs (7.2%) from metastatic tumor analysis overlapped with 1527 DEGs from the primary tumor analysis, indicating differences in host cellular targets and the viral impact between primary and metastatic NSCLC.ConclusionsThe differentially expressed genes and gene sets were distinctive among infected viral types, histological subtypes, and metastatic disease status of NSCLC. These results support the hypothesis that tumor viruses play a role in NSCLC by regulating host genes in tumor cells during NSCLC differentiation and progression.
Highlights
In our recent study, most non-small-lung cancer (NSCLC) tumor specimens harbored viral DNA but it was absent in non-neoplastic lung
A two-way hierarchical cluster analysis and a principal component analysis of all microarrays revealed that all three brain metastatic non-small cell lung cancer (NSCLC) tumor tissue specimens (one Squamous cell carcinoma (SCC) sample harboring the Y73 sarcoma virus (Y73SV) DNA, one uninfected SCC, and one uninfected adenocarcinoma samples) were clustered far apart from other primary lung tumor samples and the non-brain metastatic tumor samples, showing a brain-specific biological variation independent of viral infection status in gene expression profiles
Chen et al (2016) identified that the gain of the miRNA regulation of MIR141 to JMJD1C resulted in the gain of protein-protein interaction between JMJD1C and GADD45A in hepatocarcinogenesis that is a multistep process mainly associated with persistent infection with hepatitis B virus (HBV) or hepatitis C virus [24]
Summary
Most non-small-lung cancer (NSCLC) tumor specimens harbored viral DNA but it was absent in non-neoplastic lung. Their targets and roles in the tumor cells remain poorly understood. We analyzed gene expression microarrays to identify genes and pathways differentially altered between virus-infected and uninfected NSCLC tumors. The impact of viruses on host NSCLC tumor cells remains poorly understood and only few studies to date have investigated the roles of virus in the NSCLC [4]. Viruses can cause cellular transformation by expression of viral oncogenes, by genomic integration to alter the activity of cellular proto-oncogenes or tumor suppressor genes and by inducing inflammation that promotes oncogene activity [5]. We hypothesized that viruses in human lung cancer cells have the potential ability to affect host cells by regulating expression levels of important genes, especially oncogenes and immune-related genes
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