RESUMO
AIMS: The developmental Origins of Health and Disease (DOHaD) concept has provided the framework to assess how early life experiences can shape health and disease throughout the life course. Using a model of maternal exposure to a low protein diet (LPD; 6% protein) during the gestational and lactational periods, we demonstrated changes in the ventral prostate (VP) transcriptomic landscape in young rats exposed to maternal malnutrition. Male offspring Sprague Dawley rats were submitted to maternal malnutrition during gestation and lactation, and they were weighed, and distance anogenital was measured, followed were euthanized by an overdose of anesthesia at 21 postnatal days. Next, the blood and the ventral prostate (VP) were collected and processed by morphological analysis, biochemical and molecular analyses. RNA-seq analysis identified 411 differentially expressed genes (DEGs) in the VP of maternally malnourished offspring compared to the control group. The molecular pathways enriched by these DEGs are related to cellular development, differentiation, and tissue morphogenesis, all of them involved in both normal prostate development and carcinogenesis. Abcg1 was commonly deregulated in young and old maternally malnourished offspring rats, as well in rodent models of prostate cancer (PCa) and in PCa patients. Our results described ABCG1 as a potential DOHaD gene associated with perturbation of prostate developmental biology with long-lasting effects on carcinogenesis in old offspring rats. A better understanding of these mechanisms may help with the discussion of preventive strategies against early life origins of non-communicable chronic diseases.
Assuntos
Desnutrição , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Humanos , Masculino , Ratos , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Lactação , Desnutrição/complicações , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Próstata/metabolismo , Ratos Sprague-DawleyRESUMO
Reproductive cancers in both genders represent serious health problems, whose incidence has significantly risen over the past decades. Although considerable differences among reproductive cancers exist, we aimed to identify similar signaling pathways and key molecular oncomarkers shared among six human reproductive cancers that can advance the current knowledge of cancer biology to propose new strategies for more effective therapies. Using a computational analysis approach, here we uncover aberrant miRNAs-mRNAs networks shared in six reproductive tumor types, and identify common molecular mechanisms strictly associated with cancer promotion and aggressiveness. Based on the fact that estrogenic and androgenic signaling pathways were most active in prostate and breast cancers, we further demonstrated that both androgen and estrogen deprivation therapy are capable of regulating the expression of the same key molecular sensors associated with endoplasmic reticulum dysfunction and cell cycle in these cancers. Overall, our data reveal a potential mechanistic framework of cellular processes that are shared among reproductive cancers, and particularly, highlight the importance of hormonal deprivation in breast and prostate cancers and potentially new biomarkers of response to these therapeutic approaches.
Assuntos
Neoplasias da Mama/genética , Biologia Computacional/métodos , Neoplasias do Endométrio/genética , Redes Reguladoras de Genes , MicroRNAs/genética , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Ovarianas/genética , Neoplasias da Próstata/genética , Neoplasias Testiculares/genética , Neoplasias Uterinas/genética , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Bases de Dados Genéticas , Neoplasias do Endométrio/tratamento farmacológico , Antagonistas de Estrogênios/farmacologia , Antagonistas de Estrogênios/uso terapêutico , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Análise de Sobrevida , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológicoRESUMO
The concept of Developmental Origins of Health and Disease (DOHaD) states that exposure to malnutrition early in life increase the incidence of non-communicable chronic diseases throughout the lifespan. In this study, a reduction in serum testosterone and an increase in estrogen levels were shown in older rats born to protein malnourished dams (6% protein in the diet) during gestation and lactation. Intraprostatic levels of reduced glutathione were decreased, while tissue expression of glutathione S-transferase pi and sulfiredoxin-1 were increased in these animals. Strong immunostaining for alfametilacil CoA racemase (AMACR), vascular endothelial growth factor-A (VEGF-A), and aquaporin-1 (AQP1) was also observed. In silico analysis confirmed commonly deregulated proteins in the ventral prostate of old rats and patients with prostate cancer. In conclusion, the increase in oxidative stress associated with an imbalance of sex hormones may contribute to prostate carcinogenesis in offspring, highlighting early-life malnutrition as a key risk factor for this malignance.
