Epithelial-mesenchymal transition inhibition by metformin reduces melanoma lung metastasis in a murine model.

Melanoma is an aggressive cancer with fast metastatic spread and reduced survival time. One common event during the neoplastic progression is the epithelial-mesenchymal transition (EMT), which enhances invasiveness, cell migration, and metastasis. In this study, we investigated the effects of metformin at EMT in melanoma cell lines B16-F10 and A-375, in vitro, and the impact of EMT downregulation on melanoma progression in vivo. The metformin cells treatment reduces the migration potential in vitro and reduced the development of pulmonary metastases and the expressions of N-cadherin, vimentin, ZEB1, and ZEB2 at the metastases site, in vivo. These results indicate that metformin can promote EMT downregulation impairing the metastatic potential of melanoma cells.

Transcription factor SOX3 upregulated pro-apoptotic genes expression in human breast cancer.

BACKGROUND: Sex-determining region Y-box 3 (SOX3) protein, a SOX transcriptions factors group, has been identified as a key regulator in several diseases, including cancer. Downregulation of transcriptions factors in invasive ductal carcinoma (IDC) can interfere in neoplasia development, increasing its aggressiveness. We investigated SOX3 protein expression and its correlation with apoptosis in the MDA-MB-231 cell line, as SOX3 and Pro-Caspase-3 immunoexpression in paraffin-embedded invasive ductal carcinoma tissue samples from patients (n = 27). Breast cancer cell line MDA-MD-231 transfected with pEF1-SOX3 + and pEF1-Empty vector followed by cytotoxicity assay (MTT), Annexin-V FITC PI for apoptosis percentage assessment by flow cytometry, qPCR for apoptotic-related gene expression, immunofluorescence, and immunohistochemistry to SOX3 immunolocalization in culture cells, and paraffin-embedded invasive ductal carcinoma tissue samples. RESULTS: Apoptotic rate was higher in cells transfected with pEF1-SOX3 + (56%) than controls (10%). MDA-MB-231 transfected with pEF1-SOX3 + presented upregulation of pro-apoptotic mRNA from CASP3, CASP8, CASP9, and BAX genes, contrasting with downregulation antiapoptotic mRNA from BCL2, compared to non-transfected cells and cells transfected with pEF1-empty vector (p < 0.005). SOX3 protein nuclear expression was detected in 14% (4/27 cases) of ductal carcinoma cases, and pro-Caspase-3 expression was positive in 50% of the cases. CONCLUSION: Data suggest that SOX3 transcription factor upregulates apoptosis in breast cancer cell line MDA-MB-231, and has a down nuclear expression in ductal carcinoma cases, and need to be investigated as a tumor suppressor protein, and its loss of expression and non-nuclear action turn the cells resistant to apoptosis. Further studies are necessary to understand how SOX3 protein regulates the promoter regions of genes involved in apoptosis.

ST2 deletion accelerates inflammatory-angiogenesis and remodeling in subcutaneous implants in mice.

Implantation of biomedical/synthetic devices to replace and/or repair biological tissues very often induces an adverse healing response (scarce angiogenesis, excessive collagen deposition) which is detrimental to implant functionality and integration to host tissue. Interleukin-33/ST2 axis (IL-33/ST2) has been shown to modulate angiogenic and remodeling processes in several types of injuries. However, its effects on these processes after implantation of synthetic matrix have not been reported. Using synthetic matrix of polyether-polyurethane implanted subcutaneously in mice lacking ST2 receptor (ST2/KO), we characterized neovascularization and matrix remodeling in the fibrovascular tissue induced by the implants. Tissue accumulation was increased inside and around the implants in KO implants relative to the wild type (WT). More intense proliferative activity, using CDC 47 marker, was observed in KO implants compared with that of WT implants. Angiogenesis, using two endothelial cell markers, Von Willebrand Factor (VWF) and vascular endothelial cell VE cadherin and hemoglobin content, increased in implants of KO mice relative to control WT. Remodeling of the newly formed fibrovascular tissue (soluble collagen and PicroSirius Red-stained histological sections) showed predominance of type 1 collagen in ST2-KO implants versus type 3 in control implants. The number of positive cells for caspase-3, apoptotic marker, decreased in ST2 group. Our findings evidenced a role of IL-33/ST2 axis in restraining blood vessel formation and regulating the pattern of matrix remodeling in the fibrovascular tissue induced by synthetic implants. Intervention in this cytokine complex holds potential to accelerate integration of biomaterial and host tissue by improving blood supply and matrix remodeling.

Three new species of Gliocephalotrichum causing fruit rot on different hosts from Brazil.

The genus Gliocephalotrichum (Nectriaceae), originally described as a soil-borne fungus, has been associated with postharvest diseases, especially of tropical fruits. Taxonomic studies using both morphological and molecular phylogenetic analyses have contributed to recognition of novel species in several countries. However, in Brazil, only three isolates of Gliocephalotrichum have been collected from soil samples and roots since the late 1970s. Our study expands the sample range using many Gliocephalotrichum isolates obtained from rotting fruits of tropical plant species in different states of Brazil. Polyphasic taxonomy was assessed with phylogenetic analyses of DNA sequences from four nuclear loci, morphological comparisons, and pathogenicity tests. As a result, three known species (G. bulbilium, G. longibrachium, and G. simplex) were identified from new hosts and locations in Brazil. In addition, three new species are described-G. abrachium, G. brasiliense, and G. caryocaris. A key to all Gliocephalotrichum species worldwide is provided. Although species of Gliocephalotrichum have not been considered to be important plant pathogens, this study shows they may cause postharvest fruit rot in tropical fruits and therefore have an impact in communities that depend economically on the harvest and sale of these fruits.

Phylogenetic relationships of Phaeochorellaparinarii and recognition of a new family, Phaeochorellaceae (Diaporthales).

Species of Phaeochorella are biotrophic leaf parasites with a tropical distribution, traditionally accepted in the family Phyllachoraceae, Phyllachorales in classifications based on morphological characters. Phylogenetic evidence presented here resolves the relationship of Phaeochorella within the Sordariomycetes, based on a multilocus analysis of partial nuc rDNA large subunit (28S) and internal transcribed spacers (ITS1-5.8S-ITS2 = ITS), the DNA-directed RNA polymerase II second largest subunit (RPB2), and the translation elongation factor 1-α (TEF1-α) gene. Phylogenetic analyses indicate that Phaeochorella belongs to the Diaporthales rather than the Phyllachorales. Phaeochorella parinarii, the type species of the genus, present on native hosts from the Brazilian Cerrado, forms a unique clade with a species of Phaeoappendicospora with high support. Thus, a new family, Phaeochorellaceae, Diaporthales, including both genera, is herein proposed. With the exception of P. parinarii and P. zonata, all other species in Phaeochorella (P. artocarpi, P. ciliata, P. machaerii) were excluded from the genus.