RESUMO
Although studies have provided significant evidence about the role of RAS in mediating cancer risk in type 2 diabetes mellitus (DM), conclusions about the central molecular mechanisms underlying this disease remain to be reached, because this type of information requires an integrative multi-omics approach. In the current study, meta-analysis was performed on type 2 diabetes and breast, bladder, liver, pancreas, colon and rectum cancer-associated transcriptome data, and reporter biomolecules were identified at RNA, protein, and metabolite levels using the integration of gene expression profiles with genome-scale biomolecular networks in diabetes samples. This approach revealed that RAS biomarkers could be associated with cancer initiation and progression, which include metabolites (particularly, aminoacyl-tRNA biosynthesis and ABC transporters) as novel biomarker candidates and potential therapeutic targets. We detected downregulation and upregulation of differentially expressed genes (DEGs) in blood, pancreatic islets, liver and skeletal muscle from normal and diabetic patients. DEGs were combined with 211 renin-angiotensin-system related genes. Upregulated genes were enriched using Pathway analysis of cancer in pancreatic islets, blood and skeletal muscle samples. It seems that the changes in mRNA are contributing to the phenotypic changes in carcinogenesis, or that they are as a result of the phenotypic changes associated with the malignant transformation. Our analyses showed that Ctsg and Ednrb are downregulated in cancer samples. However, by immunohistochemistry experiments we observed that EDNRB protein showed increased expression in tumor samples. It is true that alterations in mRNA expression do not always reflect alterations in protein expression, since post-translational changes can occur in proteins. In this study, we report valuable data for further experimental and clinical analysis, because the proposed biomolecules have significant potential as systems biomarkers for screening or for therapeutic purposes in type 2 diabetes and cancer-associated pathways.
Assuntos
Diabetes Mellitus Tipo 2/genética , Perfilação da Expressão Gênica/métodos , Neoplasias/genética , Sistema Renina-Angiotensina , Catepsina G/genética , Catepsina G/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Metanálise como Assunto , Metabolômica , Neoplasias/metabolismo , Especificidade de Órgãos , Mapas de Interação de Proteínas , Proteômica , Receptor de Endotelina B/genética , Receptor de Endotelina B/metabolismoRESUMO
Here, we evaluated whether the overexpression of transcriptionally inactive ΔNp73 cooperates with PML/RARA fusion protein in the induction of an APL-leukemic phenotype, as well as its role in vitro in proliferation, myeloid differentiation, and drug-induced apoptosis. Using lentiviral gene transfer, we showed in vitro that ΔNp73 overexpression resulted in increased proliferation in murine bone marrow (BM) cells from hCG-PML/RARA transgenic mice and their wild-type (WT) counterpart, with no accumulation of cells at G2/M or S phases; instead, ΔNp73-expressing cells had a lower rate of induced apoptosis. Next, we evaluated the effect of ΔNp73 on stem-cell self-renewal and myeloid differentiation. Primary BM cells lentivirally infected with human ΔNp73 were not immortalized in culture and did not present significant changes in the percentage of CD11b. Finally, we assessed the impact of ΔNp73 on leukemogenesis or its possible cooperation with PML/RARA fusion protein in the induction of an APL-leukemic phenotype. After 120 days of follow-up, all transplanted mice were clinically healthy and, no evidence of leukemia/myelodysplasia was apparent. Taken together, our data suggest that ΔNp73 had no leukemic transformation capacity by itself and apparently did not cooperate with the PML/RARA fusion protein to induce a leukemic phenotype in a murine BM transplantation model. In addition, the forced expression of ΔNp73 in murine BM progenitors did not alter the ATRA-induced differentiation rate in vitro or induce aberrant cell proliferation, but exerted an important role in cell survival, providing resistance to drug-induced apoptosis.