RESUMO
BACKGROUND: The rapid expansion of genome-wide profiling techniques offers the opportunity to utilize various types of information collected in the study of human health and disease. Overexpression of Polo like kinase 1 (PLK1) is associated with esophageal adenocarcinoma (OAC), however biological functions and molecular targets of PLK1 in OAC are still unknown. OBJECTIVES: Here we performed integrative analysis of two "omics" data sources to reveal high-level interactions of PLK1 associated with OAC. METHODS: Initially, quantitative gene expression (RPKM) was measured from transcriptomics data set of four OAC patients. In parallel, alteration in phosphorylation levels was evaluated in the proteomics data set (mass spectrometry) in OAC cell line (PLK1 inhibited). Next, two "omics" data sets were integrated and through comprehensive analysis possible true PLK1 targets that may serve as OAC biomarkers were assembled. RESULTS: Through experimental validation, small ubiquitin-related modifier 1 (SUMO1) and heat shock protein beta-1 (HSPB1) were identified as novel phosphorylation targets of PLK1. Consequently in vivo, in situ and in silico experiments clearly demonstrated the interaction of PLK1 with putative novel targets (SUMO1 and HSPB1). CONCLUSION: Identification of a PLK1 dependent biosignature in OAC with high confidence in two omics levels proven the robustness and efficacy of our integrative approach.
Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Proteínas de Ciclo Celular/metabolismo , Neoplasias Esofágicas/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas Serina-Treonina Quinases/metabolismo , Proteoma/análise , Proteínas Proto-Oncogênicas/metabolismo , Transcriptoma , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Proteínas de Ciclo Celular/genética , Proliferação de Células , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Mapas de Interação de Proteínas , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteína SUMO-1/genética , Proteína SUMO-1/metabolismo , Células Tumorais Cultivadas , Quinase 1 Polo-LikeRESUMO
The predominance of molar teeth in fossil hominin assemblages makes the patterning of molar shape variation a topic of bioanthropological interest. Extant models are the principal basis for understanding dental variation in the fossil record. As the sister taxon to the hominin clade, Pan is one such model and the only widely accepted extant hominid model for both interspecific and intraspecific variation. To explore the contributions of allometric scaling and meristic variation to molar variation in Pan, we applied geometric shape analysis to 3D landmarks collected from virtual replicas of chimpanzee and bonobo mandibular molars. Multivariate statistical analysis and 3D visualization of metameric and allometric shape vectors were used to characterize shape differences and test the hypothesis that species of Pan share patterns of metameric variation and molar shape allometry. Procrustes-based shape variables were found to effectively characterize crown shape, sorting molars into species and tooth-row positions with ≥ 95% accuracy. Chimpanzees and bonobos share a common pattern of M(1) -M(2) metameric variation, which is defined by differences in the relative position of the metaconid, size of the hypoconulid, curvature of the buccal wall, and proportions of the basins and foveae. Allometric scaling of molar shape is homogeneous for M(1) and M(2) within species, but bonobo and chimpanzee allometric vectors are significantly different. Nevertheless, the common allometric shape trend explains most molar-shape differences between P. paniscus and P. troglodytes. When allometric effects are factored out, chimpanzee and bonobo molars are not morphometrically distinguishable. Implications for hominid taxonomy and dietary reconstruction are discussed.
