Asunto(s)
Enfermedad Crítica , Laringoscopios , Adulto , Humanos , Intubación Intratraqueal , LaringoscopíaRESUMEN
BACKGROUND: Esophageal adenocarcinoma is often considered to arise from a clonal stem-like population of cells, which is potentially responsible for its poor prognosis. Transforming growth factor ß (TGF-ß) and Notch signaling pathways play important roles in regulating self-renewal of stem cells and cell-fate determination. Both pathways are frequently implicated in gastrointestinal carcinogenesis. However, their contributions to esophageal adenocarcinoma remain unclear. METHODS: We evaluated TGF-ß and Notch signaling components in normal esophagus, Barrett's esophagus, and adenocarcinoma tissues and cell lines via immunohistochemical analysis and immunoblotting; Hes-1 transcription was assayed using a Hes-1 luciferase reporter. RESULTS: We observed loss of Smad4 (P<.05) and ß2 spectrin (ß2SP) (P<.01) in 5/10 Barrett's esophagus and 17/22 adenocarcinoma tissue sections. Concomitantly, dramatically raised levels of Notch signaling components Hes1 and Jagged1 occurred in adenocarcinoma tissues and cell lines compared with normal tissues. In normal esophagus, Oct3/4-positive cells are located in the basal layer (2-3 per cluster), representing a pool of progenitor cells. We observed an expansion of this pool of Oct3/4 positive cells in esophageal adenocarcinoma (15 per cluster). Furthermore, a panel of SOXs proteins documented for stem cell markers exhibit increased expression in tumor cells, indicating expansion of putative cancer stem cells. Finally, we observed growth inhibition in BE3 cells with a γ-secretase inhibitor, but not in SKGT-4 cells. Unlike SKGT-4 cells, BE3 cells have activated Notch signaling with disruption of TGF-ß signaling. CONCLUSIONS: Our findings demonstrated a potential therapeutic value for targeted therapy in esophageal adenocarcinoma in the setting of loss of ß2SP/TGF-ß with concomitant constitutively active Notch signaling.
Asunto(s)
Adenocarcinoma/metabolismo , Esófago de Barrett/metabolismo , Neoplasias Esofágicas/metabolismo , Esófago/metabolismo , Receptores Notch/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteínas de Unión al Calcio/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Subunidad alfa 3 del Factor de Unión al Sitio Principal , Quinasa 4 Dependiente de la Ciclina/metabolismo , Proteínas de Homeodominio/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteína Jagged-1 , Proteínas de la Membrana/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Proteínas Serrate-Jagged , Transducción de Señal , Factor de Transcripción HES-1RESUMEN
Cancer stem cells (CSCs) are critical for the initiation, propagation, and treatment resistance of multiple cancers. Yet functional interactions between specific signaling pathways in solid organ "cancer stem cells," such as those of the liver, remain elusive. We report that in regenerating human liver, two to four cells per 30,000-50,000 cells express stem cell proteins Stat3, Oct4, and Nanog, along with the prodifferentiation proteins TGF-beta-receptor type II (TBRII) and embryonic liver fodrin (ELF). Examination of human hepatocellular cancer (HCC) reveals cells that label with stem cell markers that have unexpectedly lost TBRII and ELF. elf(+/-) mice spontaneously develop HCC; expression analysis of these tumors highlighted the marked activation of the genes involved in the IL-6 signaling pathway, including IL-6 and Stat3, suggesting that HCC could arise from an IL-6-driven transformed stem cell with inactivated TGF-beta signaling. Similarly, suppression of IL-6 signaling, through the generation of mouse knockouts involving a positive regulator of IL-6, Inter-alpha-trypsin inhibitor-heavy chain-4 (ITIH4), resulted in reduction in HCC in elf(+/-) mice. This study reveals an unexpected functional link between IL-6, a major stem cell signaling pathway, and the TGF-beta signaling pathway in the modulation of mammalian HCC, a lethal cancer of the foregut. These experiments suggest an important therapeutic role for targeting IL-6 in HCCs lacking a functional TGF-beta pathway.
Asunto(s)
Interleucina-6/metabolismo , Neoplasias Hepáticas/metabolismo , Transducción de Señal , Células Madre/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Apoptosis , Proteínas de Unión al Calcio/deficiencia , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Línea Celular , Proliferación Celular , Separación Celular , Regulación hacia Abajo , Perfilación de la Expresión Génica , Glicoproteínas/deficiencia , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Hígado/citología , Hígado/metabolismo , Neoplasias Hepáticas/patología , Ratones , Ratones Noqueados , Proteínas Inhibidoras de Proteinasas Secretoras , Factor de Transcripción STAT3/metabolismoRESUMEN
Seat belt use can significantly reduce fatalities in motor vehicle crashes (Kahane, 2000). Nevertheless, the current U.S. seat belt use rate of 89.6% (Enriquez & Pickrell, 2019) indicates that a relatively small but pervasive portion of the population does not wear seat belts on a full-time basis. Whereas much is known about the demographic predictors of seat belt use, far less is understood about psychological factors that predict individual proclivities toward using or not using a seat belt. In this study, we examined some of these potential psychological predictors. A probability-based web survey was conducted with 6,038 U.S. residents aged 16 or older who reported having driven or ridden in a car in the past year. We measured self-reported seat belt use and 18 psychological constructs and found that delay of gratification, life satisfaction, risk aversion, risk perception, and resistance to peer influence were positively associated with belt use. Impulsivity and social resistance orientation were negatively associated with belt use. Prior research has shown that psychological factors like delay of gratification, risk aversion/perception, and impulsivity predict other health behaviors (e.g., cigarette smoking, sunscreen use); our results extend this literature to seat belts and can aid the development of traffic safety programs targeted at non-users who-due to such factors-may be resistant to more traditional countermeasures such as legislation and enforcement.
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Accidentes de Tránsito , Conducción de Automóvil/psicología , Adhesión a Directriz , Cinturones de Seguridad , Accidentes de Tránsito/mortalidad , Accidentes de Tránsito/prevención & control , Humanos , Influencia de los Compañeros , Cinturones de Seguridad/legislación & jurisprudencia , Cinturones de Seguridad/estadística & datos numéricos , Autoinforme , Encuestas y Cuestionarios , Heridas y Lesiones/prevención & controlRESUMEN
Transforming growth factor beta (TGF-beta) signaling has diverse and complex roles in various biological phenomena such as cell growth, differentiation, embryogenesis and morphogenesis. ES cells provide an essential model for understanding the role of TGF-beta signaling in lineage specification and differentiation. Recent studies have suggested significant role of TGF-beta in stem/progenitor cell biology. Here in this review, we focus on the role of the TGF-beta superfamily in neuronal development.