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1.
Gastroenterology ; 167(5): 903-918, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38971196

RESUMO

BACKGROUND & AIMS: WNT signaling is central to spatial tissue arrangement and regulating stem cell activity, and it represents the hallmark of gastrointestinal cancers. Although its role in driving intestinal tumors is well characterized, WNT's role in gastric tumorigenesis remains elusive. METHODS: We have developed mouse models to control the specific expression of an oncogenic form of ß-catenin (CTNNB1) in combination with MYC activation in Lgr5+ cells of the gastric antrum. We used multiomics approaches applied in vivo and in organoid models to characterize their cooperation in driving gastric tumorigenesis. RESULTS: We report that constitutive ß-catenin stabilization in the stomach has negligible oncogenic effects and requires MYC activation to induce gastric tumor formation. Although physiologically low MYC levels in gastric glands limit ß-catenin transcriptional activity, increased MYC expression unleashes the WNT oncogenic transcriptional program, promoting ß-catenin enhancer invasion without a direct transcriptional cooperation. MYC activation induces a metabolic rewiring that suppresses lysosomal biogenesis through mTOR and ERK activation and MiT/TFE inhibition. This prevents EPCAM degradation by macropinocytosis, promoting ß-catenin chromatin accumulation and activation of WNT oncogenic transcription. CONCLUSION: Our results uncovered a new signaling framework with important implications for the control of gastric epithelial architecture and WNT-dependent oncogenic transformation.


Assuntos
Molécula de Adesão da Célula Epitelial , Lisossomos , Proteínas Proto-Oncogênicas c-myc , Neoplasias Gástricas , Via de Sinalização Wnt , beta Catenina , Animais , Feminino , Humanos , Masculino , Camundongos , beta Catenina/metabolismo , beta Catenina/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Molécula de Adesão da Célula Epitelial/metabolismo , Molécula de Adesão da Célula Epitelial/genética , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Regulação Neoplásica da Expressão Gênica , Lisossomos/metabolismo , Camundongos Transgênicos , Organoides/metabolismo , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Serina-Treonina Quinases TOR/metabolismo , Transcrição Gênica
2.
Genome Res ; 28(6): 767-779, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29735605

RESUMO

Genetic and archaeological data indicate that the initial Paleoindian settlers of South America followed two entry routes separated by the Andes and the Amazon rainforest. The interactions between these paths and their impact on the peopling of South America remain unclear. Analysis of genetic variation in the Peruvian Andes and regions located south of the Amazon River might provide clues on this issue. We analyzed mitochondrial DNA variation at different Andean locations and >360,000 autosomal SNPs from 28 Native American ethnic groups to evaluate different trans-Andean demographic scenarios. Our data reveal that the Peruvian Altiplano was an important enclave for early Paleoindian expansions and point to a genetic continuity in the Andes until recent times, which was only marginally affected by gene flow from the Amazonian lowlands. Genomic variation shows a good fit with the archaeological evidence, indicating that the genetic interactions between the descendants of the settlers that followed the Pacific and Atlantic routes were extremely limited.


Assuntos
DNA Mitocondrial/genética , Fluxo Gênico/genética , Genética Populacional , Arqueologia , Cromossomos Humanos Y/genética , Etnicidade/genética , Variação Genética , Haplótipos , Humanos , Mitocôndrias/genética , Polimorfismo de Nucleotídeo Único/genética , América do Sul
3.
Int J Mol Sci ; 21(19)2020 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-33020374

RESUMO

Epigenetic aberrations have been recognized as important contributors to cancer onset and development, and increasing evidence suggests that linker histone H1 variants may serve as biomarkers useful for patient stratification, as well as play an important role as drivers in cancer. Although traditionally histone H1 levels have been studied using antibody-based methods and RNA expression, these approaches suffer from limitations. Mass spectrometry (MS)-based proteomics represents the ideal tool to accurately quantify relative changes in protein abundance within complex samples. In this study, we used a label-free quantification approach to simultaneously analyze all somatic histone H1 variants in clinical samples and verified its applicability to laser micro-dissected tissue areas containing as low as 1000 cells. We then applied it to breast cancer patient samples, identifying differences in linker histone variants patters in primary triple-negative breast tumors with and without relapse after chemotherapy. This study highlights how label-free quantitation by MS is a valuable option to accurately quantitate histone H1 levels in different types of clinical samples, including very low-abundance patient tissues.


Assuntos
Histonas/genética , Recidiva Local de Neoplasia/genética , Proteômica , Neoplasias de Mama Triplo Negativas/genética , Biomarcadores Tumorais/genética , Epigênese Genética/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Processamento de Proteína Pós-Traducional/genética , Espectrometria de Massas em Tandem , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/patologia
4.
Mol Biol Evol ; 35(2): 299-311, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29099937

RESUMO

Recent and compelling archaeological evidence attests to human presence ∼14.5 ka at multiple sites in South America and a very early exploitation of extreme high-altitude Andean environments. Considering that, according to genetic evidence, human entry into North America from Beringia most likely occurred ∼16 ka, these archeological findings would imply an extremely rapid spread along the double continent. To shed light on this issue from a genetic perspective, we first completely sequenced 217 novel modern mitogenomes of Native American ancestry from the northwestern area of South America (Ecuador and Peru); we then evaluated them phylogenetically together with other available mitogenomes (430 samples, both modern and ancient) from the same geographic area and, finally, with all closely related mitogenomes from the entire double continent. We detected a large number (N = 48) of novel subhaplogroups, often branching into further subclades, belonging to two classes: those that arose in South America early after its peopling and those that instead originated in North or Central America and reached South America with the first settlers. Coalescence age estimates for these subhaplogroups provide time boundaries indicating that early Paleo-Indians probably moved from North America to the area corresponding to modern Ecuador and Peru over the short time frame of ∼1.5 ka comprised between 16.0 and 14.6 ka.


Assuntos
Genoma Mitocondrial , Migração Humana , Indígenas Sul-Americanos/genética , Humanos , Filogenia , Filogeografia
5.
Mol Biol Evol ; 34(5): 1230-1239, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28177087

RESUMO

Sardinians are "outliers" in the European genetic landscape and, according to paleogenomic nuclear data, the closest to early European Neolithic farmers. To learn more about their genetic ancestry, we analyzed 3,491 modern and 21 ancient mitogenomes from Sardinia. We observed that 78.4% of modern mitogenomes cluster into 89 haplogroups that most likely arose in situ. For each Sardinian-specific haplogroup (SSH), we also identified the upstream node in the phylogeny, from which non-Sardinian mitogenomes radiate. This provided minimum and maximum time estimates for the presence of each SSH on the island. In agreement with demographic evidence, almost all SSHs coalesce in the post-Nuragic, Nuragic and Neolithic-Copper Age periods. For some rare SSHs, however, we could not dismiss the possibility that they might have been on the island prior to the Neolithic, a scenario that would be in agreement with archeological evidence of a Mesolithic occupation of Sardinia.


Assuntos
DNA Mitocondrial/genética , Genoma Mitocondrial/genética , DNA Antigo/análise , Demografia , Etnicidade/genética , Evolução Molecular , Variação Genética/genética , Genética Populacional/métodos , Haplótipos/genética , Humanos , Ilhas , Itália/etnologia , Filogenia , Análise de Sequência de DNA/métodos , População Branca/genética
6.
Cancer Cell ; 42(4): 662-681.e10, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38518775

RESUMO

Intratumor morphological heterogeneity of pancreatic ductal adenocarcinoma (PDAC) predicts clinical outcomes but is only partially understood at the molecular level. To elucidate the gene expression programs underpinning intratumor morphological variation in PDAC, we investigated and deconvoluted at single cell level the molecular profiles of histologically distinct clusters of PDAC cells. We identified three major morphological and functional variants that co-exist in varying proportions in all PDACs, display limited genetic diversity, and are associated with a distinct organization of the extracellular matrix: a glandular variant with classical ductal features; a transitional variant displaying abortive ductal structures and mixed endodermal and myofibroblast-like gene expression; and a poorly differentiated variant lacking ductal features and basement membrane, and showing neuronal lineage priming. Ex vivo and in vitro evidence supports the occurrence of dynamic transitions among these variants in part influenced by extracellular matrix composition and stiffness and associated with local, specifically neural, invasion.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Membrana Basal/metabolismo , Sistema Nervoso
7.
Clin Epigenetics ; 13(1): 145, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34315505

RESUMO

BACKGROUND: Increasing evidence linking epigenetic mechanisms and different diseases, including cancer, has prompted in the last 15 years the investigation of histone post-translational modifications (PTMs) in clinical samples. Methods allowing the isolation of histones from patient samples followed by the accurate and comprehensive quantification of their PTMs by mass spectrometry (MS) have been developed. However, the applicability of these methods is limited by the requirement for substantial amounts of material. RESULTS: To address this issue, in this study we streamlined the protein extraction procedure from low-amount clinical samples and tested and implemented different in-gel digestion strategies, obtaining a protocol that allows the MS-based analysis of the most common histone PTMs from laser microdissected tissue areas containing as low as 1000 cells, an amount approximately 500 times lower than what is required by available methods. We then applied this protocol to breast cancer patient laser microdissected tissues in two proof-of-concept experiments, identifying differences in histone marks in heterogeneous regions selected by either morphological evaluation or MALDI MS imaging. CONCLUSIONS: These results demonstrate that analyzing histone PTMs from very small tissue areas and detecting differences from adjacent tumor regions is technically feasible. Our method opens the way for spatial epi-proteomics, namely the investigation of epigenetic features in the context of tissue and tumor heterogeneity, which will be instrumental for the identification of novel epigenetic biomarkers and aberrant epigenetic mechanisms.


Assuntos
Histonas/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/genética , Linhagem Celular Tumoral/efeitos dos fármacos , Metilação de DNA , Histonas/genética , Humanos , Proteômica/métodos , Proteômica/estatística & dados numéricos
8.
Sci Rep ; 7(1): 9528, 2017 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-28842646

RESUMO

Genome integrity is continuously threatened by endogenous sources of DNA damage including reactive oxygen species (ROS) produced by cell metabolism. Factors of the RNA interference (RNAi) machinery have been recently involved in the cellular response to DNA damage (DDR) in proliferating cells. To investigate the impact of component of RNAi machinery on DDR activation in terminally differentiated cells, we exploited cytoplasmic hybrid (cybrid) cell lines in which mitochondria of sporadic Parkinson's disease patients repopulate neuroblastoma SH-SY5Y-Rho(0) cells. Upon differentiation into dopaminergic neuron-like cells, PD63 cybrid showed increased intracellular level of ROS and chronic DDR activation, compared to other cybrids with the same nuclear background. Importantly, DDR activation in these cells can be prevented by ROS scavenging treatment suggesting that ROS production is indeed causative of nuclear DNA damage. Sequence analysis of the mitogenomes identified a rare and heteroplasmic missense mutation affecting a highly conserved residue of the ND5-subunit of respiratory complex I, which accounts for ROS increase. We demonstrated that the assembly of nuclear DDR foci elicited by oxidative stress in these cells relies on DROSHA, providing the first evidence that components of RNAi machinery play a crucial role also in the mounting of ROS-induced DDR in non-replicating neuronal cells.


Assuntos
Dano ao DNA , Mutação de Sentido Incorreto , NADH Desidrogenase/genética , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ribonuclease III/metabolismo , Alelos , Sequência de Aminoácidos , Diferenciação Celular , Linhagem Celular , Citoplasma/metabolismo , Histonas/metabolismo , Humanos , NADH Desidrogenase/química , Fosforilação
9.
Front Genet ; 7: 208, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27933090

RESUMO

In the last 40 years, the Asian tiger mosquito Aedes albopictus, indigenous to East Asia, has colonized every continent except Antarctica. Its spread is a major public health concern, given that this species is a competent vector for numerous arboviruses, including those causing dengue, chikungunya, West Nile, and the recently emerged Zika fever. To acquire more information on the ancestral source(s) of adventive populations and the overall diffusion process from its native range, we analyzed the mitogenome variation of 27 individuals from representative populations of Asia, the Americas, and Europe. Phylogenetic analyses revealed five haplogroups in Asia, but population surveys appear to indicate that only three of these (A1a1, A1a2, and A1b) were involved in the recent worldwide spread. We also found out that a derived lineage (A1a1a1) within A1a1, which is now common in Italy, most likely arose in North America from an ancestral Japanese source. These different genetic sources now coexist in many of the recently colonized areas, thus probably creating novel genomic combinations which might be one of the causes of the apparently growing ability of A. albopictus to expand its geographical range.

10.
Sci Rep ; 6: 25472, 2016 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-27146119

RESUMO

Rare mitochondrial lineages with relict distributions can sometimes be disproportionately informative about deep events in human prehistory. We have studied one such lineage, haplogroup R0a, which uniquely is most frequent in Arabia and the Horn of Africa, but is distributed much more widely, from Europe to India. We conclude that: (1) the lineage ancestral to R0a is more ancient than previously thought, with a relict distribution across the Mediterranean/Southwest Asia; (2) R0a has a much deeper presence in Arabia than previously thought, highlighting the role of at least one Pleistocene glacial refugium, perhaps on the Red Sea plains; (3) the main episode of dispersal into Eastern Africa, at least concerning maternal lineages, was at the end of the Late Glacial, due to major expansions from one or more refugia in Arabia; (4) there was likely a minor Late Glacial/early postglacial dispersal from Arabia through the Levant and into Europe, possibly alongside other lineages from a Levantine refugium; and (5) the presence of R0a in Southwest Arabia in the Holocene at the nexus of a trading network that developed after ~3 ka between Africa and the Indian Ocean led to some gene flow even further afield, into Iran, Pakistan and India.


Assuntos
DNA Mitocondrial/genética , Fluxo Gênico , Genoma Mitocondrial , Migração Humana/história , Filogenia , Refúgio de Vida Selvagem , África Oriental , Teorema de Bayes , DNA Mitocondrial/classificação , História Antiga , Migração Humana/tendências , Humanos , Camada de Gelo , Região do Mediterrâneo , Filogeografia , Análise Espaço-Temporal
11.
PLoS One ; 10(10): e0141170, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26513361

RESUMO

BACKGROUND: Genetic studies support the scenario that Bos taurus domestication occurred in the Near East during the Neolithic transition about 10 thousand years (ky) ago, with the likely exception of a minor secondary event in Italy. However, despite the proven effectiveness of whole mitochondrial genome data in providing valuable information concerning the origin of taurine cattle, until now no population surveys have been carried out at the level of mitogenomes in local breeds from the Near East or surrounding areas. Egypt is in close geographic and cultural proximity to the Near East, in particular the Nile Delta region, and was one of the first neighboring areas to adopt the Neolithic package. Thus, a survey of mitogenome variation of autochthonous taurine breeds from the Nile Delta region might provide new insights on the early spread of cattle rearing outside the Near East. METHODOLOGY: Using Illumina high-throughput sequencing we characterized the mitogenomes from two cattle breeds, Menofi (N = 17) and Domiaty (N = 14), from the Nile Delta region. Phylogenetic and Bayesian analyses were subsequently performed. CONCLUSIONS: Phylogenetic analyses of the 31 mitogenomes confirmed the prevalence of haplogroup T1, similar to most African cattle breeds, but showed also high frequencies for haplogroups T2, T3 and Q1, and an extremely high haplotype diversity, while Bayesian skyline plots pointed to a main episode of population growth ~12.5 ky ago. Comparisons of Nile Delta mitogenomes with those from other geographic areas revealed that (i) most Egyptian mtDNAs are probably direct local derivatives from the founder domestic herds which first arrived from the Near East and the extent of gene flow from and towards the Nile Delta region was limited after the initial founding event(s); (ii) haplogroup Q1 was among these founders, thus proving that it underwent domestication in the Near East together with the founders of the T clades.


Assuntos
Genoma Mitocondrial , Genômica , Animais , Animais Domésticos , Teorema de Bayes , Cruzamento , Bovinos , Evolução Molecular , Variação Genética , Genética Populacional , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Filogenia , Filogeografia
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