RESUMO
In birds, sex is genetically determined; however, the molecular mechanism is not well-understood. The avian Z sex chromosome (chrZ) lacks whole chromosome inactivation, in contrast to the mammalian chrX. To investigate chrZ dosage compensation and its role in sex specification, we use a highly quantitative method and analyze transcriptional activities of male and female fibroblast cells from seven bird species. Our data indicate that three fourths of chrZ genes are strictly compensated across Aves, similar to mammalian chrX. We also present a complete list of non-compensated chrZ genes and identify Ribosomal Protein S6 (RPS6) as a conserved sex-dimorphic gene in birds.
Assuntos
Epigênese Genética , Cromossomos Sexuais , Animais , Feminino , Masculino , Cromossomos Sexuais/genética , Aves/genética , Fibroblastos , MamíferosRESUMO
The arachidonic acid cascade is a major inflammatory pathway that produces prostaglandin E2 (PGE2). Although inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is reported to lead to PGE2 accumulation, the role of 15-PGDH expression in the tumor microenvironment remains unclear. We utilized Panc02 murine pancreatic cancer cells for orthotopic transplantation into wild-type and 15-pgdh+/- mice and found that 15-pgdh depletion in the tumor microenvironment leads to enhanced tumorigenesis accompanied by an increase in cancer-associated fibroblasts (CAFs) and the promotion of fibrosis. The fibrotic tumor microenvironment is widely considered to be hypovascular; however, we found that the angiogenesis level is maintained in 15-pgdh+/- mice, and these changes were also observed in a genetically engineered PDAC mouse model. Further confirmation revealed that fibroblast growth factor 1 (FGF1) is secreted by pancreatic cancer cells after PGE2 stimulation, consequently promoting CAF proliferation and vascular endothelial growth factor A (VEGFA) expression in the tumor microenvironment. Finally, in 15-pgdh+/- Acta2-TK mice, depletion of fibroblasts inhibited angiogenesis and cancer cell viability in orthotopically transplanted tumors. These findings highlighted the role of 15-pgdh downregulation in enhancing PGE2 accumulation in the pancreatic tumor microenvironment and in subsequently maintaining the angiogenesis level in fibrotic tumors along with CAF expansion.
Assuntos
Neoplasias Pancreáticas , Fator A de Crescimento do Endotélio Vascular , Animais , Ácido Araquidônico , Linhagem Celular Tumoral , Dinoprostona/metabolismo , Dinoprostona/farmacologia , Fator 1 de Crescimento de Fibroblastos , Fibrose , Hidroxiprostaglandina Desidrogenases/genética , Hidroxiprostaglandina Desidrogenases/metabolismo , Camundongos , Neoplasias Pancreáticas/genética , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/genética , Neoplasias PancreáticasRESUMO
From fertilization to onset of gastrulation, a mammalian embryo goes through several rounds of cellular morphogenesis resembling phenomena of epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET), collectively referred to as EMTs. How these EMT events play a role in shaping the three-dimensional (3-D) architecture of the developing embryo is not well-understood. In this review, we present a model in which cellular morphogenesis, represented primarily by dynamic changes in its epithelialization status, is the driving force of embryonic 3-D organization. This is achieved through the integration of three key components of mammalian early development, the pluripotency regulation, morphogenetic signaling, and biomechanical force anisotropy. Although cells in an early embryo do not exhibit full mesenchymal characteristics, our model underscores the importance of investigating molecular regulation of epithelial cell polarity and partial EMT/MET in understanding mammalian early development.