ABSTRACT
Despite tremendous advances in targeted therapies against lung adenocarcinoma, the majority of patients do not benefit from personalized treatments. A deeper understanding of potential therapeutic targets is crucial to increase the survival of patients. One promising target, ADAR, is amplified in 13% of lung adenocarcinomas and in-vitro studies have demonstrated the potential of its therapeutic inhibition to inhibit tumor growth. ADAR edits millions of adenosines to inosines within the transcriptome, and while previous studies of ADAR in cancer have solely focused on protein-coding edits, >99% of edits occur in non-protein coding regions. Here, we develop a pipeline to discover the regulatory potential of RNA editing sites across the entire transcriptome and apply it to lung adenocarcinoma tumors from The Cancer Genome Atlas. This method predicts that 1413 genes contain regulatory edits, predominantly in non-coding regions. Genes with the largest numbers of regulatory edits are enriched in both apoptotic and innate immune pathways, providing a link between these known functions of ADAR and its role in cancer. We further show that despite a positive association between ADAR RNA expression and apoptotic and immune pathways, ADAR copy number is negatively associated with apoptosis and several immune cell types' signatures.
Subject(s)
Adenocarcinoma/genetics , Adenosine Deaminase/metabolism , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Lung Neoplasms/genetics , RNA, Neoplasm/genetics , RNA-Binding Proteins/metabolism , 3' Untranslated Regions/genetics , Adenocarcinoma of Lung , Adenosine Deaminase/genetics , Apolipoprotein L1/genetics , Apoptosis/genetics , Gene Amplification , Gene Dosage , Humans , Immunity, Innate/genetics , RNA Editing , RNA, Neoplasm/metabolism , RNA-Binding Proteins/genetics , Survival AnalysisABSTRACT
Triclosan is an antimicrobial chemical incorporated into many personal, medical and household products. Approximately, 75% of the U.S. population has detectable levels of triclosan in their urine, and although it is not typically considered a contact sensitizer, recent studies have begun to link triclosan exposure with augmented allergic disease. We examined the effects of dermal triclosan exposure on the skin and lymph nodes of mice and in a human skin model to identify mechanisms for augmenting allergic responses. Triclosan (0%-3%) was applied topically at 24-h intervals to the ear pinnae of OVA-sensitized BALB/c mice. Skin and draining lymph nodes were evaluated for cellular responses and cytokine expression over time. The effects of triclosan (0%-0.75%) on cytokine expression in a human skin tissue model were also examined. Exposure to triclosan increased the expression of TSLP, IL-1ß, and TNF-α in the skin with concomitant decreases in IL-25, IL-33, and IL-1α. Similar changes in TSLP, IL1B, and IL33 expression occurred in human skin. Topical application of triclosan also increased draining lymph node cellularity consisting of activated CD86(+)GL-7(+) B cells, CD80(+)CD86(+) dendritic cells, GATA-3(+)OX-40(+)IL-4(+)IL-13(+) Th2 cells and IL-17 A(+) CD4 T cells. In vivo antibody blockade of TSLP reduced skin irritation, IL-1ß expression, lymph node cellularity, and Th2 responses augmented by triclosan. Repeated dermal exposure to triclosan induces TSLP expression in skin tissue as a potential mechanism for augmenting allergic responses.
Subject(s)
Anti-Infective Agents, Local/toxicity , Cytokines/biosynthesis , Dermatitis, Allergic Contact/pathology , Stromal Cells/metabolism , Th2 Cells/drug effects , Th2 Cells/immunology , Triclosan/toxicity , Adaptive Immunity/drug effects , Administration, Topical , Animals , Dermatitis, Allergic Contact/immunology , Humans , In Vitro Techniques , Lymph Nodes/drug effects , Mice , Mice, Inbred BALB C , Stromal Cells/drug effects , Thymic Stromal LymphopoietinABSTRACT
In an earlier report, Platek et al. (1985) presented the results of an 18-month inhalation exposure of rats and monkeys to short chrysotile asbestos. The mean chamber exposure level was 1.0 mg/m(3) with an average of 0.79 fibers/ml > 5 microm in length. Gross and histopathological examination of exposed and control rats indicated no treatment-related lesions. Asbestos bodies adjacent to the terminal bronchioles, but no fibrosis, were found in lung biopsy tissue taken from the exposed monkeys at 10 months post-exposure. Fifteen monkeys (9 exposed and 6 controls) from this study were maintained for 11.5 years following exposure. Lung fiber burdens were determined by transmission electron microscopy. The mean lung burden (+/- standard deviation) for 59 samples from exposed monkeys was 63 +/- 30 x 10(6) fibers/g dry lung (range, 18-139 x 10(6)). The geometric mean fiber length was 3.5 microm with 35% of the fibers being > 5 microm in length. These data indicate some chrysotile fibers are durable in vivo for a significant period of time. Lungs were examined grossly and microscopically. No lesions attributable to the inhalation exposure were noted. Asbestos bodies were seen in the lungs of treated monkeys, primarily in the interstitium near bronchioles or small pulmonary blood vessels (which also may have been near to bronchioles just out of the plane of section).
