RESUMEN
Bladder cancer, the most common malignancy of the urinary tract, has a poor overall survival rate when the tumor becomes muscle invasive. The discovery and evaluation of new alternative medications targeting high-grade muscle invasive bladder cancer (MIBC) are of tremendous importance in reducing bladder cancer mortality. Isorhapontigenin (ISO), a stilbene derivative from the Chinese herb Gnetum cleistostachyum, exhibits a strong anti-cancer effect on MIBCs. Here, we report the whole transcriptome profiling of ISO-treated human bladder cancer T24 cells. A total of 1047 differentially expressed genes (DEGs) were identified, including 596 downregulated and 451 upregulated genes. Functional annotation and pathway analysis revealed that ISO treatment induced massive changes in gene expression associated with cell movement, migration, invasion, metabolism, proliferation, and angiogenesis. Additionally, ISO treatment-activated genes involved in the inflammatory response but repressed genes involved in hypoxia signaling, glycolysis, the actin cytoskeleton, and the tumor microenvironment. In summary, our whole transcriptome analysis demonstrated a shift in metabolism and altered actin cytoskeleton in ISO-treated T24 cells, which subsequently contribute to tumor microenvironment remodeling that suppresses tumor growth and progression.
Asunto(s)
Estilbenos , Neoplasias de la Vejiga Urinaria , Humanos , Línea Celular Tumoral , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Estilbenos/farmacología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Transcriptoma , Microambiente TumoralRESUMEN
Lung cancer is the leading cause of cancer-related death worldwide; however, the mechanism of lung carcinogenesis has not been clearly defined. Chronic exposure to hexavalent chromium [Cr(VI)], a common environmental and occupational pollutant, causes lung cancer, representing an important lung cancer etiology factor. The mechanism of how chronic Cr(VI) exposure causes lung cancer remains largely unknown. By using cell culture and mouse models and bioinformatics analyses of human lung cancer gene expression profiles, this study investigated the mechanism of Cr(VI)-induced lung carcinogenesis. A new mouse model of Cr(VI)-induced lung carcinogenesis was developed as evidenced by the findings showing that a 16-week Cr(VI) exposure (CaCrO4, 100 µg per mouse once per week) via oropharyngeal aspiration induced lung adenocarcinomas in male and female A/J mice, whereas none of the sham-exposed control mice had lung tumors. Mechanistic studies revealed that chronic Cr(VI) exposure activated the non-canonical NFκB pathway through the long non-coding RNA (lncRNA) ABHD11-AS1/deubiquitinase USP15-mediated tumor necrosis factor receptor-associated factor 3 (TRAF3) down-regulation. The non-canonical NFκB pathway activation increased the interleukin 6 (IL-6)/Janus kinase (Jak)/signal transducer and activator of transcription 3 (Stat3) signaling. The activation of the IL-6/Jak signaling axis by Cr(VI) exposure not only promoted inflammation but also stabilized the immune checkpoint molecule programmed death-ligand 1 (PD-L1) protein in the lungs, reducing T lymphocyte infiltration to the lungs. Given the well-recognized critical role of PD-L1 in inhibiting anti-tumor immunity, these findings suggested that the lncRNA ABHD11-AS1-mediated non-canonical NFκB pathway activation and PD-L1 up-regulation may play important roles in Cr(VI)-induced lung carcinogenesis.
Asunto(s)
Cromo , Neoplasias Pulmonares , ARN Largo no Codificante , Animales , Femenino , Humanos , Masculino , Ratones , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Carcinogénesis/patología , Transformación Celular Neoplásica/genética , Proteínas de Punto de Control Inmunitario/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Ligandos , Pulmón/patología , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , FN-kappa B/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Serina Proteasas/metabolismo , Proteasas Ubiquitina-Específicas/metabolismoRESUMEN
BACKGROUND: Pyrotechnic displays often lead to significant increases in poor air quality. The widespread environmental fate-involving air, water, and spatial-temporal analyses-of fireworks-produced pollutants has seldom been investigated. OBJECTIVE: This study examined the environmental fate of pollutants from the largest fireworks event in the U.S.: Macy's Fourth of July Fireworks show in New York City (NYC). METHODS: Real-time PM2.5 and gravimetric PM2.5 and PM10 were collected at locations along the East River of NYC. Airborne particles were assayed for trace elements (X-ray fluorescence) and organic and elemental carbon (OC/EC). River water samples were evaluated by ICP-MS for heavy-metal water contamination. Spatial-temporal analyses were created using PM2.5 concentrations reported by both EPA and PurpleAir monitoring networks for NYC and 5 other major metropolitan areas. RESULTS: The fireworks event resulted in large increases in PM2.5 mass concentrations at the river-adjacent sampling locations. While background control PM2.5 was 10-15 µg/m3, peak real-time PM2.5 levels exceeded 3000 µg/m3 at one site and 1000 µg/m3 at two other locations. The integrated gravimetric PM2.5 and PM10 concentrations during the fireworks event ranged from 162 to 240 µg/m3 and 252 to 589 µg/m3, respectively. Zn, Pb, Sb, and Cu more than doubled in river water samples taken after the event, while S, K, Ba, Cu, Mg, Fe, Sr, Ti, and Zn increased in airborne PM2.5 from the fireworks. Data from hyperlocal monitoring networks for NYC and other metropolitan areas yielded similar, but generally smaller, increases in PM2.5 levels. IMPACT: Fireworks shows have been associated with environmental contamination. This comprehensive analysis considers the fate of pollutants from the largest annual U.S. pyrotechnic show through air, water, and hyperlocal temporal characterization.