RESUMO
Persistent colonization of the gastric mucosa by Helicobacter pylori (Hp) elicits chronic inflammation and aberrant epithelial cell proliferation, which increases the risk of gastric cancer. Here we examine the ability of microRNAs to modulate gastric cell proliferation in response to persistent Hp infection and find that epigenetic silencing of miR-210 plays a key role in gastric disease progression. Importantly, DNA methylation of the miR-210 gene is increased in Hp-positive human gastric biopsies as compared with Hp-negative controls. Moreover, silencing of miR-210 in gastric epithelial cells promotes proliferation. We identify STMN1 and DIMT1 as miR-210 target genes and demonstrate that inhibition of miR-210 expression augments cell proliferation by activating STMN1 and DIMT1. Together, our results highlight inflammation-induced epigenetic silencing of miR-210 as a mechanism of induction of chronic gastric diseases, including cancer, during Hp infection.
Assuntos
Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Infecções por Helicobacter/genética , Metiltransferases/metabolismo , MicroRNAs/metabolismo , Estatmina/metabolismo , Neoplasias Gástricas/genética , Animais , Ciclo Celular/genética , Proliferação de Células , Doença Crônica , Metilação de DNA , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Células Epiteliais/patologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Perfilação da Expressão Gênica , Gerbillinae , Infecções por Helicobacter/complicações , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/patogenicidade , Helicobacter pylori/fisiologia , Humanos , Masculino , Metiltransferases/genética , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Análise de Sequência com Séries de Oligonucleotídeos , Cultura Primária de Células , Regiões Promotoras Genéticas , Ligação Proteica , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Estatmina/genética , Neoplasias Gástricas/complicações , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologiaRESUMO
Mice lacking the lymphocyte-specific transcription factor Bob1 (also called OBF-1 or OCA-B) fail to generate germinal centers and a robust Ig response. We show that peripheral B cells in Bob1(-/-) mice bear characteristics of chronically activated or anergic-like B cells and identify the immunosuppressive microRNA-146a, together with other microRNAs, as novel transcriptional targets of Bob1. The inability to restrict B cell signaling could contribute to the immunodeficient phenotype of these mice and is consistent with an important role for Bob1 in suppressing B cell activation in vivo.
Assuntos
Linfócitos B/imunologia , Ativação Linfocitária/fisiologia , MicroRNAs/imunologia , Transdução de Sinais/fisiologia , Transativadores/imunologia , Animais , Linfócitos B/citologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , MicroRNAs/genética , Transativadores/genéticaRESUMO
Proper regulation of gene expression during cell cycle entry ensures the successful completion of proliferation, avoiding risks such as carcinogenesis. The microRNA (miRNA) network is an emerging molecular system regulating multiple genetic pathways. We demonstrate here that the global elevation of miRNAs is critical for proper control of gene expression program during cell cycle entry. Strikingly, Exportin 5 (XPO5) is promptly induced during cell cycle entry by a PI3K-dependent post-transcriptional mechanism. Inhibition of XPO5 induction interfered with global miRNA elevation and resulted in a proliferation defect associated with delayed G1/S transition. During cell cycle entry, XPO5 therefore plays a paramount role as a critical molecular hub controlling the gene expression program through global regulation of miRNAs. Our data suggest that XPO5-mediated global miRNA elevation might be involved in a broad range of cellular events associated with cell cycle control.
Assuntos
Ciclo Celular , Carioferinas/metabolismo , MicroRNAs/genética , Animais , Fibroblastos/metabolismo , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/metabolismo , Neoplasias/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Transdução de SinaisRESUMO
The cancer stem cell theory suggests that chemoresistance and recurrence of tumors are often due to the similarity of stem cell properties between normal and cancer cells. Adult T-cell leukemia/lymphoma (ATLL) has poor prognosis, suggesting that ATLL cells possess common stem cell properties. We analyzed side population (SP), a characteristic stem cell phenotype, and CD markers in ATLL cell lines. We found that several lines contained SP with expressions of some hematopoietic stem cell markers. On the other hand, treatment with interferon (IFN)-alpha is sometimes effective in ATLL, particularly combined with other drugs. We examined its effect on ATLL cells and found that IFN-alpha significantly reduced the SP proportion. Moreover, CD25-positive cells and phosphorylation of STAT1/5 and ERK were upregulated during this process. These data suggest that their stem cell properties render ATLL cells therapy-resistant, and IFN-alpha exerts its clinical effect through a reduction of the SP cell population.
