Expression of LEF1 and TCF1 (TCF7) proteins associates with clinical progression of nasopharyngeal carcinoma.

AIMS: Our previous study has demonstrated that ß-catenin pathway was abnormally activated in nasopharyngeal carcinoma (NPC). The purposes of the present study are to investigate whether the alterations of LEF1 and TCF1 (TCF7) proteins, the important components of the canonical Wnt/ß-catenin pathway, are associated with clinicopathological features and prognostic implications. METHODS: We collected 391 cases of NPC, 53 non-cancerous control nasopharyngeal mucosa and 28 pairs of NPC and their matched metastases, detected expression of LEF1 and TCF1 (TCF7) proteins in these tissues by immunohistochemistry.  RESULTS: Results showed that there were significantly increased expression of both LEF1 and TCF1 (TCF7) proteins and coexpression of LEF1 and TCF1 (TCF7) in NPC than these in non-cancerous nasopharyngeal mucosa (all p<0.001), as well as LEF1 and coexpression of LEF1 and TCF1 (TCF7) in matched metastasis NPCs than these in the primary NPCs (p=0.003 and p=0.014, respectively). In addition, expression of LEF1 and the coexpression of LEF1 and TCF1 (TCF7) proteins were positively correlated with lymph node metastasis (p=0.001 and p=0.020, respectively), advanced clinical stage (p<0.003 and p=0.027, respectively) and poor survival status of patients with NPC (p<0.001 and p=0.004, respectively). Moreover, multivariate Cox regression analysis identified that the positive expression of LEF1 was the independent poor prognostic factor for overall survival of patients with NPC (p<0.001). CONCLUSIONS: The expression of LEF1 associated positively with TCF1 (TCF7) and clinical progression of NPC, and positive expression of LEF1 protein may act as valuable independent biomarker to predict poor prognosis for patients with NPC.

The significant increase and dynamic changes of the myeloid-derived suppresor cells percentage with chemotherapy in advanced NSCLC patients

PURPOSE: To investigate the correlations between myeloid-derived suppressor cells (MDSCs) in the peripheral blood and cancer stage, immune function, and chemotherapy. METHODS: Percentages of MDSCs (CD11b(+)CD14(-)CD33(+) cells) and lymphocyte subsets in peripheral blood mononuclear cells (PBMCs) of 94 patients with Non-small cell lung cancer (NSCLC) who were treated naïve and 30 healthy individuals were measured. Changes of the MDSCs percentage were further detected in patients with advanced NSCLC treated with systemic chemotherapy. Finally, coculture with CD8(+) cells was developed to determine effect of MDSCs on IFN-γ secretion of T lymphocytes. RESULTS: MDSCs percentage of 94 patients with NSCLC was significantly higher than that of 30 healthy subjects (P < 0.05), the percentages were increased with tumor progression, in patients with stage III and IV percentages were significantly higher than those in stage I and II patients (P = 0.013). The MDSCs percentage was negatively related to percentage of CD8(+) cells in the peripheral blood (r = -0.354, n = 38, P = 0.029), and when they were cocultured, IFN-γ secretion of CD8(+) cells was significantly decreased (P < 0.05). In 20 patients with advanced NSCLC who received systemic chemotherapy, nine partial remission (PR) cases got MDSCs percentage significantly decreased (P < 0.001), three stable disease (SD) cases remained invariable (P = 0.307) and eight progressive disease (PD) cases got significantly increased (P = 0.024). CONCLUSION: The percentage of MDSCs in the patients was significantly higher than that of the healthy control subjects and it increased with tumor progression partially by inhibiting the CD8(+) cell function. The dynamic changes of MDSCs percentage reflected the efficacy of systemic chemotherapy (AU)

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Wnt signaling transcription factors TCF-1 and LEF-1 are upregulated in malignant astrocytic brain tumors.

Since the discovery of the TCF/LEF family of transcription factors, their functions have been under intensive investigation in the area of cancer biology. The work presented in this paper focused on the changes in TCF-1 and LEF-1 expression levels in a set of astrocytic brain tumors. Protein expression was detected using immunohistochemistry and then evaluated by Ellipse software (ViDiTo, Slovakia). Statistical evaluations were performed with the SPSS statistical package, version 14.0 (SPSS Inc., Chicago, IL, USA). Strong TCF-1 and LEF-1 expression was observed in 51.6% and 71% of glioblastoma samples. Statistical analysis confirmed significant differences in protein expression levels associated to 3 important values, weak expression of TCF-1, weak expression of LEF-1 and strong expression of LEF-1. Analysis of variances performed on the total sample also indicated significant differences in the values of TCF-1 weak (F=2.804; p=0.045), LEF-1 weak (F=4.255; p=0.008) and LEF-1 strong (F=5.498; p=0.002) with regard to malignancy grade. Thus, glioblastomas were characterized by -in relative terms- the lowest values for weak expression of TCF-1 and LEF-1, combined with the highest values of LEF-1 strong expression. The F-ratios for two variables (LEF-1 strong and LEF-1 weak) indicated that differences between astrocytomas (II, III) and glioblastomas were statistically significant (p<0.02). Discriminant function analysis further showed that strong LEF-1 expression alone could discriminate between astrocytomas (II, III) and glioblastomas. Elevated TCF-1 and LEF-1 expression is characteristic of malignant gliomas. LEF-1, in particular, may serve as a potential marker for malignant transformation.

Wnt/ß-catenin pathway regulates bone morphogenetic protein (BMP2)-mediated differentiation of dental follicle cells.

BACKGROUND AND OBJECTIVE: Bone morphogenetic protein 2 (BMP2)-induced osteogenic differentiation has been shown to occur through the canonical Wnt/ßcatenin pathway, whereas factors promoting canonical Wnt signaling in cementoblasts inhibit cell differentiation and promote cell proliferation in vitro. The aim of this study was to investigate whether putative precursor cells of cementoblasts, dental follicle cells (murine SVF4 cells), when stimulated with BMP2, would exhibit changes in genes/proteins associated with the Wnt/ß-catenin pathway. MATERIAL AND METHODS: SVF4 cells were stimulated with BMP2, and the following assays were carried out: (i) Wnt/ß-catenin pathway activation assessed by western blotting, ß-catenin/transcription factor (TCF) reporter assays and expression of the lymphoid enhancer-binding factor-1 (Lef1), transcription factor 7 (Tcf7), Wnt inhibitor factor 1 (Wif1) and Axin2 (Axin2) genes; and (ii) cementoblast/osteoblast differentiation assessed by mineralization in vitro, and by the mRNA levels of runt-related transcription factor 2 (Runx2), osterix (Osx), alkaline phosphatase (Alp), osteocalcin (Ocn) and bone sialoprotein (Bsp), determined by quantitative PCR after treatment with wingless-type MMTV integration site family, member 3A (WNT3A) and knockdown of ß-catenin. RESULTS: WNT3A induced ß-catenin nuclear translocation and up-regulated the transcriptional activity of a canonical Wnt-responsive reporter, suggesting that the Wnt/ß-catenin pathway functions in SVF4 cells. Activation of Wnt signaling with WNT3A suppressed BMP2-mediated induction of cementoblast/osteoblast maturation of SVF4 cells. However, ß-catenin knockdown showed that the BMP2-induced expression of cementoblast/osteoblast differentiation markers requires endogenous ß-catenin. WNT3A down-regulated transcripts for Runx2, Alp and Ocn in SVF4 cells compared with untreated cells. In contrast, BMP2 induction of Bsp transcripts occurred independently of Wnt/ß-catenin signaling. CONCLUSION: These data suggest that stabilization of ß-catenin by WNT3A inhibits BMP2-mediated induction of cementoblast/osteoblast differentiation in SVF4 cells, although BMP2 requires endogenous Wnt/ß-catenin signaling to promote cell maturation.