RESUMEN
Telomerase activation is one of the key mechanisms that allow cells to bypass replicative senescence. Telomerase activity is primarily regulated at the level of transcription of its catalytic unit- hTERT. Prostate cancer (PCa), akin to other cancers, is characterized by high telomerase activity. Existing data suggest that hTERT expression and telomerase activity are positively regulated by androgenic stimuli in androgen-dependent prostate cancer (ADPC) cells. A part of the present study reaffirmed this by demonstrating a decline in the hTERT expression and telomerase activity on "loss of AR" in ADPC cells. The study further addressed 2 unresolved queries, i) whether AR-mediated signaling is of any relevance to hTERT expression in castration-resistant prostate cancer (CRPC) and ii) whether this signaling involves EGR1. Our data suggest that AR-mediated signaling negatively regulates hTERT expression in CRPC cells. Incidental support for the possibility of EGR1 being a regulator of hTERT expression in PCa was provided by i) immunolocalization of hTERT and EGR1 proteins in the same cell type (secretory epithelium) of PCa and BPH tissues; ii) significantly (p< 0.001) higher levels of both these proteins in CRPC (PC3 and DU145), compared with ADPC (LNCaP) cells. A direct evidence for the role of EGR1 in hTERT expression was evident by a significant (p<0.0001) decrease in the hTERT transcript levels in the EGR1-silenced CRPC cells. Further, "gain of AR" led to a significant reduction in the levels of hTERT and EGR1 in CRPC cells. However, restoration of EGR1 levels prevented the decline in the hTERT transcript levels in these cells. Taken together, our data indicate that AR regulates the expression of EGR1, which in turn acts as a positive regulator of hTERT expression in CRPC cells. Thus, AR exerts an inhibitory effect on hTERT expression and telomerase activity by modulating EGR1 levels in CRPC cells.
Asunto(s)
Anticuerpos Monoclonales/metabolismo , Neoplasias de la Próstata/genética , Receptores Androgénicos/metabolismo , Telomerasa/metabolismo , Línea Celular Tumoral , Proliferación Celular , Humanos , Masculino , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Transducción de SeñalRESUMEN
Myelodysplastic syndromes (MDSs) are heterogeneous hematopoietic disease characterized by ineffective haematopoiesis that frequently transforms into acute leukaemia. Alterations in many individual biologic pathways have been reported in MDS pathophysiology. Disease progression along the MDS, acute myeloid leukemia (AML) continuum is believed to be a consequence of stepwise accumulation of DNA mutations which infers a defect in DNA repair. The present study investigated the association between DNA repair genes (XRCC1, XRCC3, OGG1, XPD and RAD51) and the risk of developing MDS. The study was carried out in 92 primary MDS patients. The genotyping study was carried out by PCR-RFLP technique. We have studied seven single-nucleotide polymorphisms (SNPs) of five DNA repair genes (XRCC1 (Arg194Trp, Arg280His, Arg399Gln), XRCC3, XPD, RAD51 and OGG1). Significantly, a high frequency of DNA repair gene XRCC1 (Arg280His) (p=0.05) and XPD (Lys751Gln) (p=0.01) polymorphism was observed in MDS patients compared to controls. The distribution of polymorphisms in MDS subgroups showed a significant association of XRCC1 with RAEB I compared to other subgroup. Though a high frequency of XRCC1 gene polymorphism was observed in farmers and tobacco chewers, it was not statistically significant. Our study suggests that XRCC1 (Arg280His) and XPD polymorphisms are associated with risk of MDS and XRCC1 polymorphism strongly associated with advanced MDS subgroup. Hence, these polymorphisms can be used as a prognostic marker in MDS.
Asunto(s)
Proteínas de Unión al ADN/genética , Estudios de Asociación Genética , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Polimorfismo de Nucleótido Simple/genética , Proteína de la Xerodermia Pigmentosa del Grupo D/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Arginina/genética , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética/métodos , Glutamina/genética , Histidina/genética , Humanos , Lisina/genética , Masculino , Persona de Mediana Edad , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X , Adulto JovenRESUMEN
Chronic myeloid leukemia (CML) occurs due to t(9,22) (q34;q11) and molecularly BCR/ABL gene fusion. About 15-18% Philadelphia positive CML patients have gene deletions around the translocation breakpoints on 9q34.1. The microRNAs (miRNAs), namely miR-219-2 and miR-199b, centromeric to the ABL1 gene are frequently lost in CML patients. We have designed a study to determine miR-219-2 and miR-199b expression levels which would help to understand the prognosis of imatinib therapy. A total of 150 CML patients were analyzed to identify 9q deletion. Fluorescent in-situ hybridization (FISH) was performed using BCR/ABL dual color, dual fusion probe to study the signal pattern and BAC probes for miR-199b and miR-219-2 (RP11-339B21 and RP11-395P17) to study the miRNA deletions. The expression level of miRNA was analyzed by real-time polymerase chain reaction (RT-PCR). FISH analysis revealed 9q34.1 deletion in 34 (23%) CML patients. The deletions were not detected using BAC probes for miRNAs in 9q deleted patients. The expression analysis showed down-regulation of miR-199b and miR-219-2 in the 9q deleted patients (34 CML) as compared to a pool of patients without deletion. However, miR-199b (9q34.11) was significantly (p=0.001) down-regulated compared to miR-219-2. The follow-up study showed that the miR-199b was found to be strongly associated with imatinib resistance, as 44.11% patients showed resistance to imatinib therapy. Hence, the deletion in 9q34.1 region (ABL) plays an important role in disease pathogenesis. Eventually, miRNAs can provide new therapeutic strategies and can be used as a prognostic indicator.
Asunto(s)
Benzamidas/uso terapéutico , Cromosomas Humanos Par 9 , Resistencia a Antineoplásicos/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , MicroARNs/genética , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Adolescente , Adulto , Anciano , Niño , Preescolar , Deleción Cromosómica , Cromosomas Artificiales Bacterianos , Regulación hacia Abajo , Femenino , Proteínas de Fusión bcr-abl/genética , Regulación Leucémica de la Expresión Génica , Humanos , Mesilato de Imatinib , Hibridación Fluorescente in Situ , Lactante , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder that occurs because of t(9;22)(q34;q11) translocations. Complex translocations have been reported in CML. We report a novel 5-way translocation 46,XY,t(9;11;13;19;22)(9q34.12;11p11.12;13q21.31;19q13.12;22q11.21) using GTG banding, fluorescence in situ hybridization, and spectral karyotyping in a case of chronic-phase CML. Molecular analysis revealed the presence of 2 types of transcripts (b3a2, b2a2). The patient was responding to the imatinib treatment. However, the patient needs to be carefully monitored at various intervals.
Asunto(s)
Cromosomas Humanos Par 11 , Cromosomas Humanos Par 13 , Cromosomas Humanos Par 19 , Cromosomas Humanos Par 22 , Cromosomas Humanos Par 9 , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Translocación Genética/genética , Adulto , Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 19/genética , Cromosomas Humanos Par 22/genética , Cromosomas Humanos Par 9/genética , Humanos , Mesilato de Imatinib , Hibridación Fluorescente in Situ , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Cariotipificación Espectral , Resultado del TratamientoRESUMEN
MicroRNAs (miRNAs) are about 19-24 nucleotide small single-stranded noncoding RNAs that are involved in crucial cell processes such as proliferation, apoptosis, and differentiation. Several studies reported show the involvement of miRNA in cancer. It has been suggested that miRNA profiling has the potential to classify a variety of tumors and possibly predict outcome. MicroRNA can act as an oncogene as well as tumor suppressor gene and this dual function of miRNA can be utilized as a therapeutic tool. The oncogenic character of miRNA can be silenced through various RNA interference-type strategies. The involvement of miRNA in the tumorogenesis processes makes them an important therapeutic tool and a novel biomarker. In this review, we have highlighted the role of miRNA in hematological malignancies and its utility in targeted therapy.