RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers among all solid tumors. First-line treatment relies on gemcitabine (Gem) and despite treatment improvements, refractoriness remains a universal challenge. Attempts to decipher how feedback-loops control signaling pathways towards drug resistance have gained attention in recent years, particularly focused on the role of phosphatases. In this study, a CRISPR/Cas9-based phenotypic screen was performed to identify members from the dual-specificity phosphatases (DUSP) family potentially acting on Gem response in PDAC cells. The approach revealed the atypical RNA phosphatase DUSP11 as a potential target, whose inhibition creates vulnerability of PDAC cells to Gem. DUSP11 genetic inhibition impaired cell survival and promoted apoptosis, synergistically enhancing Gem cytotoxicity. In silico transcriptome analysis of RNA-seq data from PDAC human samples identified NF-ĸB signaling pathway highly correlated with DUSP11 upregulation. Consistently, Gem-induced NF-ĸB phosphorylation was blocked upon DUSP11 inhibition in vitro. Mechanistically, we found that DUSP11 directly impacts nc886 expression and modulates PKR-NF-ĸB signaling cascade after Gem exposure in PDAC cells resulting in resistance to Gem-induced cell death. In conclusion, this study provides new insights on DUSP11 role in RNA biology and Gem response in PDAC cells.

Asunto(s)

Desoxicitidina , Fosfatasas de Especificidad Dual , Gemcitabina , FN-kappa B , Neoplasias Pancreáticas , Humanos , Apoptosis/efectos de los fármacos , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Fosfatasas de Especificidad Dual/genética , Fosfatasas de Especificidad Dual/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/metabolismo , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , FN-kappa B/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología

RESUMEN

Identifying the genetic factors that underlie complex traits is central to understanding the mechanistic underpinnings of evolution. Cave-dwelling Astyanax mexicanus populations are well adapted to subterranean life and many populations appear to have evolved troglomorphic traits independently, while the surface-dwelling populations can be used as a proxy for the ancestral form. Here we present a high-resolution, chromosome-level surface fish genome, enabling the first genome-wide comparison between surface fish and cavefish populations. Using this resource, we performed quantitative trait locus (QTL) mapping analyses and found new candidate genes for eye loss such as dusp26. We used CRISPR gene editing in A. mexicanus to confirm the essential role of a gene within an eye size QTL, rx3, in eye formation. We also generated the first genome-wide evaluation of deletion variability across cavefish populations to gain insight into this potential source of cave adaptation. The surface fish genome reference now provides a more complete resource for comparative, functional and genetic studies of drastic trait differences within a species.

Asunto(s)

Adaptación Fisiológica/genética , Characidae/embriología , Characidae/genética , Ojo/embriología , Herencia Multifactorial/genética , Animales , Evolución Biológica , Cuevas , Mapeo Cromosómico , Evolución Molecular , Edición Génica , Genoma/genética , Proteínas de Homeodominio/genética , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , Sitios de Carácter Cuantitativo/genética

RESUMEN

African American women are disproportionately affected by type 2 diabetes. Genetic factors may explain part of the excess risk. More than 100 genetic variants have been associated with risk of type 2 diabetes, but most studies have been conducted in white populations. Two genome-wide association studies (GWAS) in African Americans have identified three novel genetic variants only. We conducted admixture mapping using 2918 ancestral informative markers in 2632 cases of type 2 diabetes, and 2596 controls nested in the ongoing Black Women's Health Study cohort, with the goal of identifying genomic loci with local African ancestry associated with type 2 diabetes. In addition, we performed replication analysis of 71 previously identified index SNPs, and fine-mapped those genetic loci to identify better or new genetic variants associated with type 2 diabetes in African Americans. We found that individual African ancestry was associated with higher risk of type 2 diabetes. In addition, we identified two genomic regions, 3q26 and 12q23, with excess of African ancestry associated with higher risk of type 2 diabetes. Lastly, we replicated 8 out of 71 index SNPs from previous GWAS, including, for the first time in African Americans, the X-linked rs5945326 SNP near the DUSP9 gene. In addition, our fine-mapping efforts suggest independent signals at five loci. Our detailed analysis identified two genomic regions associated with risk of type 2 diabetes, and showed that many genetic risk variants are shared across ancestries.

Asunto(s)

Negro o Afroamericano/genética , Mapeo Cromosómico , Diabetes Mellitus Tipo 2/genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 3/genética , Fosfatasas de Especificidad Dual/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Persona de Mediana Edad , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética

RESUMEN

Mitogen-activated protein kinases (MAPK) are integration points for multiple biochemical signals. We evaluated 13 MAPK genes with breast cancer risk and determined if diet and lifestyle factors mediated risk. Data from 3 population-based case-control studies conducted in Southwestern United States, California, and Mexico included 4183 controls and 3592 cases. Percent Indigenous American (IA) ancestry was determined from 104 ancestry informative markers. The adaptive rank truncated product (ARTP) was used to determine the significance of each gene and the pathway with breast cancer risk, by menopausal status, genetic ancestry level, and estrogen receptor (ER)/progesterone receptor (PR) strata. MAP3K9 was associated with breast cancer overall (P(ARTP) = 0.02) with strongest association among women with the highest IA ancestry (P(ARTP) = 0.04). Several SNPs in MAP3K9 were associated with ER+/PR+ tumors and interacted with dietary oxidative balance score (DOBS), dietary folate, body mass index (BMI), alcohol consumption, cigarette smoking, and a history of diabetes. DUSP4 and MAPK8 interacted with calories to alter breast cancer risk; MAPK1 interacted with DOBS, dietary fiber, folate, and BMI; MAP3K2 interacted with dietary fat; and MAPK14 interacted with dietary folate and BMI. The patterns of association across diet and lifestyle factors with similar biological properties for the same SNPs within genes provide support for associations.

Asunto(s)

Neoplasias de la Mama/genética , Dieta/estadística & datos numéricos , Estilo de Vida , Proteínas Quinasas Activadas por Mitógenos/genética , Adulto , Anciano , Índice de Masa Corporal , Neoplasias de la Mama/etnología , Neoplasias de la Mama/metabolismo , Estudios de Casos y Controles , Grasas de la Dieta/metabolismo , Fibras de la Dieta/metabolismo , Fosfatasas de Especificidad Dual/genética , Ingestión de Energía/genética , Femenino , Ácido Fólico/metabolismo , Disparidades en el Estado de Salud , Humanos , MAP Quinasa Quinasa Quinasa 2 , Quinasas Quinasa Quinasa PAM/genética , Menopausia/genética , México/epidemiología , Persona de Mediana Edad , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 14 Activada por Mitógenos/genética , Proteína Quinasa 8 Activada por Mitógenos/genética , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , Polimorfismo de Nucleótido Simple/genética , Grupos de Población/genética , Receptores de Estrógenos/sangre , Receptores de Progesterona/sangre , Sistema de Registros , Factores de Riesgo , San Francisco , Sudoeste de Estados Unidos