RESUMO
Multiple sequential genetic and epigenetic alterations underlie cancer development and progression. Overcoming cellular senescence is an early step in cancer pathogenesis. Here, we demonstrate that a noncoding regulatory RNA, microRNA-16 (miR-16), has the potential to induce cellular senescence. First, we examined the expression of miR-16 in primary cutaneous T-cell lymphoma (CTCL) and other non-Hodgkin T/natural killer (NK)-cell lymphomas and found that miR-16 was downregulated than that in the corresponding normal cells. Notably, miR-16 expression was reduced as the primary CTCL progressed from the early stage to the advanced stage. Next, we transduced CTCL cells with miR-16 to examine whether this miRNA exhibited tumor-suppressive effects in CTCL cells. In CTCL cells expressing wild-type p53, forced expression of miR-16 enhanced p21 expression via downregulation of the polycomb group protein Bmi1, thereby inducing cellular senescence. Alternatively, in CTCL cells lacking functional p53, miR-16 induced compensatory apoptosis. The miR-16 transfection significantly decreased senescent cells and increased apoptotic cells in p21-knockdown CTCL cells expressing wild-type p53, suggesting that the presence or absence of p21 may be the most important condition in the senescence-apoptosis switch in CTCL lymphomagenesis. Furthermore, we found that the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) restored the expression of miR-16 and its essential targets, induced senescence in CTCL cells expressing wild-type p53 and promoted apoptosis in cells with nonfunctional p53. Moreover, we found that other T/NK-cell lymphoma cell lines showed similar tumor-suppressive effects in response to miR-16 and SAHA and that these effects were dependent on p53 status. These results suggested that epigenetic silencing of miR-16 may be a key step during lymphoma development. Elucidation of the essential targets of miR-16 and SAHA provides a basis for the clinical application of SAHA in the treatment of CTCL and other non-Hodgkin T/NK-cell lymphomas.
Assuntos
Apoptose/genética , Senescência Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Linfoma não Hodgkin/genética , Linfoma Cutâneo de Células T/genética , MicroRNAs/genética , Animais , Western Blotting , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/patologia , Linfoma Cutâneo de Células T/metabolismo , Linfoma Cutâneo de Células T/patologia , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Heterólogo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , VorinostatRESUMO
The frequency of serological cross-reactions between Ibaraki (IB), and bluetongue (BT) viruses using the agar gel immunodiffusion (AGID) test was investigated. The percentage of IB neutralisation-positive bovine serum samples that were positive to the BT AGID test was 42.5%; 12.2% of the BT AGID-positive serum samples and 2.5% of the BT AGID-negative serum samples were positive to the IB AGID test. When the BT competitive ELISA (c-ELISA) was used, these cross-reactions disappeared. These results indicate that serum samples from areas in which IB is epidemic are often positive against the BT AGID test, but negative against the BT virus neutralisation test (VNT). To obtain specific BT surveillance results in these IB endemic areas, the AGID-positive results should be confirmed using the c-ELISA or VNT.
