RESUMEN
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.
Asunto(s)
Apoptosis/genética , Senescencia Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Linfoma no Hodgkin/genética , Linfoma Cutáneo de Células T/genética , MicroARNs/genética , Animales , Western Blotting , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Ácidos Hidroxámicos/farmacología , Linfoma no Hodgkin/metabolismo , Linfoma no Hodgkin/patología , Linfoma Cutáneo de Células T/metabolismo , Linfoma Cutáneo de Células T/patología , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Trasplante Heterólogo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , VorinostatRESUMEN
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.
