Non-Hodgkin lymphoma. Here, by immunohistochemical analysis of a tissue-microarray including 170 NHLs, we found that PATZ1 nuclear expression is usually down-regulated in follicular lymphomas and DLBCLs. Moreover, consistent with our previous results showing a PATZ1-dependent regulation of BCL6 and BAX transcription, we show that low PATZ1 nuclear expression significantly correlates with high BCL6 expression, mainly in DLBCLs, and with low BAX expression, also considering separately follicular lymphomas and DLBCLs. Finally, by analyzing overall and progression-free survival in DLBCL patients that underwent rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, low levels of PATZ1 were significantly associated to a worst outcome and exhibited an independent prognostic factor in multivariate analysis, including known prognostic factors of DLBCL, IPI score and cell of origin (GCB/non-GCB). Therefore, we propose PATZ1 as a new prognostic marker of DLBCLs, which may act as a tumor suppressor by enhancing apoptosis through inhibiting and enhancing transcription of BCL6 and BAX, respectively. gene has been associated to different Rabbit Polyclonal to TF2H1 types of malignancy sometimes working as a tumor suppressor and sometimes as an oncogene, depending on the cellular context [14C17]. As for other members of the POK family, PATZ1 plays important functions in development and malignancy through its involvement in a variety of cellular processes, including cell proliferation, DNA repair, senescence, apoptosis and differentiation [16C22]. In most of these processes it acts upstream and downstream of p53, suggesting it could be a key regulator of the p53 pathway [16, 18, 22]. The tumor suppressor gene is usually directly regulated by BCL6, which represses its transcription in GCB DLBCLs [23] and its inactivation has been correlated with a poor prognosis in patients with DLBCL treated with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP) therapy or rituximab plus CHOP (R-CHOP) [24]. Here, we performed immunohistochemical staining of a Tissue-Micro-Array (TMA), including 170 cases of NHLs, to investigate the expression of PATZ1, BCL6 and the p53/PATZ1 target BAX and their reciprocal correlations with respect to the different histotype and sub-type. To finally assess the impact of PATZ1 expression on patients’ end result, we TAK-715 analysed overall (OS) and progression-free (PFS) survival of DLBCL patients treated with R-CHOP, including a public dataset of 470 patients from your MD Anderson Malignancy Center [25], other than 65 patients from our TMA series. We found that low PATZ1 (either gene or protein) expression significantly correlates with poor survival, suggesting PATZ1 as a negative prognostic marker for this heterogeneous malignancy. RESULTS Tissue-micro-array design and Clinicopathological data One hundred and seventy tissue samples were utilized for a TMA building, using three tissue cores taken from two to three discrete but representative regions of each single case. The main clinicopathological data of the 170 cases of NHL included in the TMA are set out in Table ?Table1.1. The series included 83 (48.8%) males and 87 (51.2%) females, with a mean age of 59.9 +/? 14 (Standard deviation). In our histological samples, there were 70 (41.2%) FLs and 100 (58.8%) DLBCLs. Moreover, DLBCLs included 47 GCB (47%) and 53 non-GCB (53%). Table 1 Clinicopathological characteristics = 170)- In the NHL group, BCL6 expression negatively correlates with PATZ1 expression, being PATZ1 more expressed in the BCL6 low samples than in the BCL6 high ones (= 0.013 and 0.014; Pearson and Mann-Whitney tests, respectively) (Physique ?(Figure2);2); this correlation is not significant in the TAK-715 FL group (= 1 and 0.559; Pearson and Mann-Whitney assessments, respectively) (Physique ?(Figure3),3), but it is in the DLBCL group (= 0.009 and 0.006; Pearson and Mann-Whitney assessments, respectively), with a trend to be negatively correlated in both non-GCB and GCB sub-types (Figures ?(Figures44 and ?and5).5). These data are consistent with the inhibition of BCL6 transcription by PATZ1 in human DLBCLs. Open in a separate window Physique 5 Immunophenotype of DLBCLsSerial sections of two representative cases of DLBCL were stained for BCL6, BAX and PATZ1: Case 1 (A, B, C) is usually BCL6 unfavorable (A), BAX positive (B) and PATZ1 positive (C); Case 2 (D, E, F) is usually BCL6 positive (D), BAX negative (E) and PATZ1 negative (F). Scale bars: 50 m. – In the NHL group, TAK-715 low PATZ1 expression significantly correlates with low BAX expression ( 0.001 by both Pearson and Mann-Whitney assessments) (Figure ?(Figure2);2); this correlation is usually significant both in the FL group (= 0.015 and 0.009; Pearson and Mann-Whitney assessments, respectively) (Physique ?(Determine3)3) and in the DLBCL group ( 0.001 by both Pearson and Mann-Whitney assessments), with non-GCB (= 0.001 and 0.01; Pearson and Mann-Whitney assessments, respectively) and GCB ( 0.001 by both Pearson and Mann-Whitney assessments) (Figures ?(Figures44 and ?and5).5). These data are consistent with the enhancement of BAX transcription.