RESUMO
AIMS: Ying Yang 1 (YY1) is a transcription factor involved in both proliferation and apoptosis. It is prognostic in follicular lymphoma (FL), increased protein levels being associated with favourable outcome. PLK1 is a critical regulator of mitosis, playing a role in spindle formation and in regulation of the G2/M cell cycle checkpoint. PLK1 phosphorylates YY1 at the G2/M checkpoint with activation of YY1 and resultant progression from G2 into mitosis. METHODS: This study aims to investigate possible molecular coexpression and interaction of YY1 with PLK1 in FL using Duolink II in situ proximity ligation assay (PLA) in 51 FL samples in a tissue microarray. RESULTS: Positive PLA signals were present at variable frequency and Kaplan-Meier analysis showed association of signal frequency above the median with unfavourable outcome (p=0.0270). PLA signals were localised to the nuclear edge, with only one signal per cell, suggesting PLK1 and YY1 coexpression at the centrosome. In a minority of cells, two very close PLA signals were present in a single cell, and occasionally, there was a strong ring of semi-confluent fluorescent PLA signals round the nucleus of non-dividing cells, while rarely events were observed in the cytoplasm surrounding dividing cells. CONCLUSIONS: The results confirm association of YY1 and PLK1 with outcome in FL and suggest coexpression at the centrosome. Given the reported interaction of YY1 with PLK1 at the centriole and promotion of cell division at the G2/M checkpoint, the results would concord with the known association of higher proliferation with poor outcome in FL.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Linfonodos/metabolismo , Linfoma Folicular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Fator de Transcrição YY1/metabolismo , Adulto , Idoso , Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Centrossomo/metabolismo , Feminino , Humanos , Linfonodos/patologia , Linfoma Folicular/genética , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Mitose/genética , Fosforilação , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Análise de Sobrevida , Taxa de Sobrevida , Fator de Transcrição YY1/genética , Quinase 1 Polo-LikeRESUMO
AIMS: Follicular lymphoma is the second most common type of non-Hodgkin's lymphoma worldwide. The majority of patients diagnosed as having follicular lymphoma have an indolent form of the disease, but a subset of patients have aggressive disease with a shorter survival interval. Optimal treatment stratification requires a distinction between these two groups, though there are presently few prognostic biomarkers available. The transcription factor YY1 has been shown to play an important role in cancer biology. The authors have previously reported a correlation of Yin Yang 1 (YY1) mRNA levels with survival in FL. This study aimed to validate these findings at the protein level. METHODS: Quantification of YY1 protein was carried out on 26 FL biopsy samples using quantum dot labelled immunohistochemistry. Ki-67 percentage, grade, YY1 protein levels and T cell and macrophage markers were used in a multivariable analysis for survival in 26 cases of FL. RESULTS: Expression levels of YY1 protein were significantly increased in patients alive in comparison with those dead after follow-up (p ≤ 0.025). Kaplan-Meier analysis showed association of higher expression levels of YY1 with longer survival (p ≤ 0.01) (hazard ratio 3.33, 95% CI 1.26 to 8.85). The multivariable analysis identified YY1 protein level as the strongest predictor of outcome (p ≤ 0.018), with none of the other markers being significantly associated with outcome. CONCLUSION: These results support the prognostic utility of YY1 in FL, indicating potential as a clinical biomarker.