Clinical significance of T-bet, GATA-3, and Bcl-6 transcription factor expression in bladder carcinoma

International audienceBackground: The aim of this study was to investigate the clinical significance of three immune cell-related transcription factors, T-bet, GATA-3 and Bcl-6 in bladder cancer in Tunisian patients.Methods: Expression of T-bet, GATA-3 and Bcl-6 genes was assessed using RT-qPCR in 65 bladder cancers from patients: 32 being diagnosed as low-and medium-grade, 31 as high-grade, 25 as muscle invasive stage and 39 as non-muscle invasive stage. Gene expression was statistically correlated according to the grade, the stage, tobacco consumption, the BCG response and disease severity.Results: T-bet levels in patients with high-grade bladder cancer were significantly elevated compared to patients with low-or medium-grade bladder cancer (p = 0.005). In invasive carcinoma (T2-T4), the T-bet levels were significantly higher than in superficial non-invasive bladder tumors (Tis, Ta, and T1) (p = 0.02). However, T-bet is predictive of the response to BCG. Its expression is high in good responders to BCG (p = 0.02). In contrast, the expression of GATA-3 and Bcl-6 in non-invasive carcinoma (p = 0.008 and p = 0.0003) and in patients with low-and medium-grade cancers (p = 0.001 and p < 0.0001) is significantly higher than in invasive bladder tumors and in patients with high-grade bladder carcinoma, respectively. In addition, heavy smokers, whose tumors express low levels of GATA-3 and Bcl-6, are poor responders to BCG (p = 0.01 and p = 0.03). Finally, better patient survival correlated with GATA-3 (p = 0.04) and Bcl-6 (p = 0.04) but not T-bet expression.Conclusions: Our results suggest that T-bet expression in bladder tumors could be a positive prognostic indicator of BCG therapy, even if high levels are found in high-grade and stage of the disease. However, GATA-3 and Bcl-6 expression could be considered as predictive factors for good patient survival

Research of prognostic biomarkers in Tunisian patients with bladder cancer

Le cancer de la vessie représente un vrai problème de santé publique, avec une surveillance et suivi clinique à long terme en raison de l’importance des fréquences de récidives. La chimiothérapie reste souvent inefficace. L’objectif de cette thèse est donc la recherche de marqueurs sérologiques et moléculaires à valeur pronostique dans le cancer de la vessie qui peuvent servir à prédire la maladie. D’abord, nous avons étudié trois facteurs de transcriptions des lymphocytes T activées qui sont T-bet, GATA-3 et Bcl-6. Nous avons montré une surexpression de T-bet chez les malades à stade invasif et de haut grade, cependant, la surexpression de GATA-3 et Bcl-6 a été corrélée au stade superficiel et de bas grade. La survie a été corrélée avec le groupe des malades sans histoires de récidive ou progression et avec la surexpression de Bcl-6 et GATA-3. Cependant les malades qui expriment fortement T-bet répondent mieux au BCG. Ensuite, nous avons visé la détection de FasL et TRAIL solubles dans le sérum des malades atteints du cancer vésicale. Nous avons montré une surexpression de sFasL et sTRAIL chez les malades à stade superficiel et de bas grade. Le rôle anti-tumoral de ces cytokines a été confirmé sur deux lignées du cancer de la vessie montrant que le traitement avec le sérum riche en sFasL ou en sTRAIL diminue la viabilité cellulaire in vitro. A la fin de cette thèse, nous avons testé l’activation p-Akt dans la tumeur vésicale. Nous avons montré une surexpression de p-Akt au sein des tumeurs comparées au tissu sain adjacent, et au sein des malades à stade invasif et de haut grade. Akt semble être un marqueur de progression tumorale dans le cancer de la vessie.Bladder cancer is the first most common urogenital cancer in men in Tunisia, with a high recurrence rate. Patients with muscle-invasive disease develop metastasis. The need for expensive continuous surveillance. In this thesis we try to search some candidate biomarkers. Their use for cancer staging and personalization of therapy at the time of diagnosis in order to identify a better treatment could improve patient care. The aim of this first part of our study was to investigate the clinical significance of three immune cell-related transcription factors, T-bet, GATA-3 and Bcl-6 in Tunisian patients with bladder cancer. We found that T-bet level was significantly higher in invasive carcinoma with high- grade. However, T-bet is predictive of response to BCG. On the contrary, the expression of GATA-3 and Bcl-6 was significantly higher in non-invasive carcinoma with low grade. We furthermore studied the effect of activation of soluble FasL and TRAIL molecule in bladder cancer. We demonstrate that the mean serum level of sFasL was higher in patients than in normal donors. sFasL was only higher than in sera of healthy donors where patients had superficial stage and low- and medium-grade cancer. sTRAIL was significantly lower in sera from patients with invasive and high-grade bladder carcinoma than in controls. Finally, we demonstrate that p-Akt levels in patients with invasive carcinoma and high-grade bladder cancer were significantly elevated compared to patients with non-invasive and low grade bladder cancer. Altogether, our results suggest that Akt activation can provide useful prognostic information

Recherche de biomarqueurs pronostiques dans le cancer de la vessie dans la population Tunisienne

Bladder cancer is the first most common urogenital cancer in men in Tunisia, with a high recurrence rate. Patients with muscle-invasive disease develop metastasis. The need for expensive continuous surveillance. In this thesis we try to search some candidate biomarkers. Their use for cancer staging and personalization of therapy at the time of diagnosis in order to identify a better treatment could improve patient care. The aim of this first part of our study was to investigate the clinical significance of three immune cell-related transcription factors, T-bet, GATA-3 and Bcl-6 in Tunisian patients with bladder cancer. We found that T-bet level was significantly higher in invasive carcinoma with high- grade. However, T-bet is predictive of response to BCG. On the contrary, the expression of GATA-3 and Bcl-6 was significantly higher in non-invasive carcinoma with low grade. We furthermore studied the effect of activation of soluble FasL and TRAIL molecule in bladder cancer. We demonstrate that the mean serum level of sFasL was higher in patients than in normal donors. sFasL was only higher than in sera of healthy donors where patients had superficial stage and low- and medium-grade cancer. sTRAIL was significantly lower in sera from patients with invasive and high-grade bladder carcinoma than in controls. Finally, we demonstrate that p-Akt levels in patients with invasive carcinoma and high-grade bladder cancer were significantly elevated compared to patients with non-invasive and low grade bladder cancer. Altogether, our results suggest that Akt activation can provide useful prognostic information.Le cancer de la vessie représente un vrai problème de santé publique, avec une surveillance et suivi clinique à long terme en raison de l’importance des fréquences de récidives. La chimiothérapie reste souvent inefficace. L’objectif de cette thèse est donc la recherche de marqueurs sérologiques et moléculaires à valeur pronostique dans le cancer de la vessie qui peuvent servir à prédire la maladie. D’abord, nous avons étudié trois facteurs de transcriptions des lymphocytes T activées qui sont T-bet, GATA-3 et Bcl-6. Nous avons montré une surexpression de T-bet chez les malades à stade invasif et de haut grade, cependant, la surexpression de GATA-3 et Bcl-6 a été corrélée au stade superficiel et de bas grade. La survie a été corrélée avec le groupe des malades sans histoires de récidive ou progression et avec la surexpression de Bcl-6 et GATA-3. Cependant les malades qui expriment fortement T-bet répondent mieux au BCG. Ensuite, nous avons visé la détection de FasL et TRAIL solubles dans le sérum des malades atteints du cancer vésicale. Nous avons montré une surexpression de sFasL et sTRAIL chez les malades à stade superficiel et de bas grade. Le rôle anti-tumoral de ces cytokines a été confirmé sur deux lignées du cancer de la vessie montrant que le traitement avec le sérum riche en sFasL ou en sTRAIL diminue la viabilité cellulaire in vitro. A la fin de cette thèse, nous avons testé l’activation p-Akt dans la tumeur vésicale. Nous avons montré une surexpression de p-Akt au sein des tumeurs comparées au tissu sain adjacent, et au sein des malades à stade invasif et de haut grade. Akt semble être un marqueur de progression tumorale dans le cancer de la vessie

Akt activation correlates with the tumor aggressiveness in Tunisian patients with bladder cancer

International audienceVarious studies in western countries found Akt amplification to be a frequent event in human cancers, including bladder, but the correlation with clinicopathological features is controversial. Such studies have not been reported in African populations, including Tunisians. The purpose of this study was to assess expression of the phosphorylated/activated forms of Akt in tumors from Tunisian patients with bladder cancer and to correlate its expression with pathological and clinical parameters of the disease. The study included 72 patients of whom 34 were diagnosed as low- to medium-grade and 35 as high-grade; 30 were muscle stage and 39 non-muscle stage. Primary tumors from these patients, normal adjacent tissues, or bladder cancer cell-lines were analyzed for Ser473 phosphorylated Akt expression by Western blot. Seventy-two percent of primary tumors from patients with bladder cancer had increased levels of p-Akt. The p-Akt levels in patients with high-grade bladder cancer were significantly elevated compared to patients with low- or medium-grade bladder cancer. In invasive carcinoma, the p-Akt level was significantly higher than in superficial non-invasive bladder tumors. Concerning the influence of tobacco on Akt activation, no significant differences of p-Akt expression were found between non-smoker and smoker patients. Altogether, our results suggest that Akt activation can provide useful prognostic information and that tobacco represents a serious risk factor for recurrence in a cohort of Tunisian patients