RESUMO
Although the role of miR-200s in regulating E-cadherin expression and epithelial-to-mesenchymal transition is well established, their influence on metastatic colonization remains controversial. Here we have used clinical and experimental models of breast cancer metastasis to discover a pro-metastatic role of miR-200s that goes beyond their regulation of E-cadherin and epithelial phenotype. Overexpression of miR-200s is associated with increased risk of metastasis in breast cancer and promotes metastatic colonization in mouse models, phenotypes that cannot be recapitulated by E-cadherin expression alone. Genomic and proteomic analyses revealed global shifts in gene expression upon miR-200 overexpression toward that of highly metastatic cells. miR-200s promote metastatic colonization partly through direct targeting of Sec23a, which mediates secretion of metastasis-suppressive proteins, including Igfbp4 and Tinagl1, as validated by functional and clinical correlation studies. Overall, these findings suggest a pleiotropic role of miR-200s in promoting metastatic colonization by influencing E-cadherin-dependent epithelial traits and Sec23a-mediated tumor cell secretome.
Assuntos
Regulação Neoplásica da Expressão Gênica/fisiologia , MicroRNAs/metabolismo , Metástase Neoplásica/fisiopatologia , Proteínas de Transporte Vesicular/metabolismo , Animais , Caderinas/metabolismo , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Humanos , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos BALB C , Análise em Microsséries , Estatísticas não ParamétricasRESUMO
Aggressive angiomyxoma is a rare vulvovaginal, perineal or pelvic mesenchymal neoplasm with a marked tendency to local recurrence but does not metastasize. A case of an aggressive angiomyxoma of vulva in a 39-years-old women with an illness of one year prior to examination, with a slow and progressive growth of the left vulvar region, without other symptoms. During physical examination, a piriform tumor of 15x10 cm was found, located on the left labia majora, soft tissue dependent. Wide resection of the tumor were performed. Hystopathology reported an aggressive angiomyxoma of the vulva, with tumor in resection margins. The patient was treated with a 65Gy postsurgical radiotherapy and gosereline 3.6 mg monthly, during 6 cycles. Aggressive angiomyxoma is a rare neoplasm 150 cases has been reported. The treatment is surgical resection. Radiotherapy and hormonal adyuvant is not fully stablished.
Assuntos
Mixoma/patologia , Neoplasias Vulvares/patologia , Adulto , Feminino , Humanos , Mixoma/terapia , Neoplasias Vulvares/terapiaRESUMO
Targeted therapy for metastatic diseases relies on the identification of functionally important metastasis genes from a large number of random genetic alterations. Here we use a computational algorithm to map minimal recurrent genomic alterations associated with poor-prognosis breast cancer. 8q22 genomic gain was identified by this approach and validated in an extensive collection of breast tumor samples. Regional gain of 8q22 elevates expression of the metastasis gene metadherin (MTDH), which is overexpressed in more than 40% of breast cancers and is associated with poor clinical outcomes. Functional characterization of MTDH revealed its dual role in promoting metastatic seeding and enhancing chemoresistance. These findings establish MTDH as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk.
Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Moléculas de Adesão Celular/metabolismo , Cromossomos Humanos Par 8/genética , Resistencia a Medicamentos Antineoplásicos , Genoma Humano/genética , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/metabolismo , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Humanos , Proteínas de Membrana , Camundongos , Camundongos Nus , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-met , Proteínas de Ligação a RNA , Receptores de Fatores de Crescimento/genética , Receptores de Fatores de Crescimento/metabolismo , Taxa de Sobrevida , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The orchid genus Maxillaria is one of the largest and most common of neotropical orchid genera, but its current generic boundaries and relationships have long been regarded as artificial. Phylogenetic relationships within subtribe Maxillariinae sensu Dressler (1993) with emphasis on Maxillaria s.l. were inferred using parsimony analyses of individual and combined DNA sequence data. We analyzed a combined matrix of nrITS DNA, the plastid matK gene and flanking trnK intron, and the plastid atpB-rbcL intergenic spacer for 619 individuals representing ca. 354 species. The plastid rpoC1 gene (ca. 2600 bp) was sequenced for 84 selected species and combined in a more limited analysis with the other data sets to provide greater resolution. In a well-resolved, supported consensus, most clades were present in more than one individual analysis. All the currently recognized minor genera of "core" Maxillariinae (Anthosiphon, Chrysocycnis, Cryptocentrum, Cyrtidiorchis, Mormolyca, Pityphyllum, and Trigonidium) are embedded within a polyphyletic Maxillaria s.l. Our results support the recognition of a more restricted Maxillaria, of some previously published segregate genera (Brasiliorchis, Camaridium, Christensonella, Heterotaxis, Ornithidium, Sauvetrea), and of several novel clades at the generic level. These revised monophyletic generic concepts should minimize further nomenclatural changes, encourage monographic studies, and facilitate more focused analyses of character evolution within Maxillariinae.