Tobacco Smoke and Electronic Cigarette Vapor Alter Enhancer RNA Expression That Can Regulate the Pathogenesis of Lung Squamous Cell Carcinoma.

Tobacco is the primary etiologic agent in worsened lung squamous cell carcinoma (LUSC) outcomes. Meanwhile, it has been shown that etiologic agents alter enhancer RNAs (eRNAs) expression. Therefore, we aimed to identify the effects of tobacco and electronic cigarette (e-cigarette) use on eRNA expression in relation to LUSC outcomes. We extracted eRNA counts from RNA-sequencing data of tumor/adjacent normal tissue and before/after e-cigarette tissue from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), respectively. Tobacco-mediated LUSC eRNAs were correlated to patient survival, clinical variables, and immune-associated elements. eRNA expression was also correlated to mutation rates through the Repeated Evaluation of Variables Conditional Entropy and Redundance (REVEALER) algorithm and methylated sites through methylationArrayAnalysis. Differential expression analysis was then completed for the e-cigarette data to compare with key tobacco-mediated eRNAs. We identified 684 downregulated eRNAs and 819 upregulated eRNAs associated with tobacco-mediated LUSC, specifically, with the cancer pathological stage. We also observed a decrease in immune cell abundance in tobacco-mediated LUSC. Yet, we found an increased association of eRNA expression with immune cell abundance in tobacco-mediated LUSC. We identified 16 key eRNAs with significant correlations to 8 clinical variables, implicating these eRNAs in LUSC malignancy. Furthermore, we observed that these 16 eRNAs were highly associated with chromosomal alterations and reduced CpG site methylation. Finally, we observed large eRNA expression upregulation with e-cigarette use, which corresponded to the upregulation of the 16 key eRNAs. Our findings provide a novel mechanism by which tobacco and e-cigarette smoke influences eRNA interactions to promote LUSC pathogenesis and provide insight regarding disease progression at a molecular level.

Influence of Intratumor Microbiome on Clinical Outcome and Immune Processes in Prostate Cancer.

Although 1 in 9 American men will receive a diagnosis of prostate cancer (PC), most men with this diagnosis will not die from it, as most PCs are indolent. However, there is a subset of patients in which the once-indolent PC becomes metastatic and eventually, fatal. In this study, we analyzed microbial compositions of intratumor bacteria in PC to determine the influence of the microbiome on metastatic growth. Using large-scale RNA-sequencing data and corresponding clinical data, we correlated the abundance of microbes to immune pathways and PC risk factors, identifying specific microbes that either significantly deter or contribute to cancer aggressiveness. Interestingly, most of the microbes we found appeared to play anti-tumor roles in PC. Since these anti-tumor microbes were overrepresented in tumor samples, we believe that microbes thrive in the tumor microenvironment, outcompete cancer cells, and directly mitigate tumor growth by recruiting immune cells. These include Listeria monocytogenes, Methylobacterium radiotolerans JCM 2831, Xanthomonas albilineans GPE PC73, and Bradyrhizobium japonicum, which are negatively correlated with Gleason score, Tumor-Node-Metastasis (TNM) stage, prostate-specific antigen (PSA) level, and Androgen Receptor (AR) expression, respectively. We also identified microbes that contribute to tumor growth and are positively correlated with genomic alterations, dysregulated immune-associated (IA) genes, and prostate cancer stem cells (PCSC) genes.

Tobacco, but Not Nicotine and Flavor-Less Electronic Cigarettes, Induces ACE2 and Immune Dysregulation.

The COVID-19 pandemic caused by the SARS-CoV-2 virus, overlaps with the ongoing epidemics of cigarette smoking and electronic cigarette (e-cig) vaping. However, there is scarce data relating COVID-19 risks and outcome with cigarette or e-cig use. In this study, we mined three independent RNA expression datasets from smokers and vapers to understand the potential relationship between vaping/smoking and the dysregulation of key genes and pathways related to COVID-19. We found that smoking, but not vaping, upregulates ACE2, the cellular receptor that SARS-CoV-2 requires for infection. Both smoking and use of nicotine and flavor-containing e-cigs led to upregulation of pro-inflammatory cytokines and inflammasome-related genes. Specifically, chemokines including CCL20 and CXCL8 are upregulated in smokers, and CCL5 and CCR1 are upregulated in flavor/nicotine-containing e-cig users. We also found genes implicated in inflammasomes, such as CXCL1, CXCL2, NOD2, and ASC, to be upregulated in smokers and these e-cig users. Vaping flavor and nicotine-less e-cigs, however, did not lead to significant cytokine dysregulation and inflammasome activation. Release of inflammasome products, such as IL-1B, and cytokine storms are hallmarks of COVID-19 infection, especially in severe cases. Therefore, our findings demonstrated that smoking or vaping may critically exacerbate COVID-19-related inflammation or increase susceptibility to COVID-19.