Aim: To evaluate the relationship between telomere length (TL), telomerase activity and telomere-binding proteins (TBP) and grading and recurrence rate in patients with superficial bladder cancer (SBC). Patients and Methods: In 35 patients (tumor group; age: 63.9±10.6 years) with SBC, samples from the bladder tumor and disease-free bladder mucosa were obtained. In the control group of 23 healthy individuals (age: 65.3±10.1 years), samples from the bladder mucosa were collected. In all samples, TL was detected by Southern blot, while the expression of hTERT and of several TBP (TRF1, TRF2, PARP1 and TANK) were detected by Western blot. Histological examination was carried out on all samples. The patients underwent immuno- or chemotherapy, and for all of them, cytoscopy was performed at 3, 6 and 12 months. Statistical analysis of the results was performed using the parametric ANOVA test and the post-hoc Bonferroni test. Statistically significant results were considered when p<0.05. Results: The histological examination in the tumor group revealed 15 (42.9%) high-grade (HG) SBC and 20 (57.1%) low-grade (LG) SBC. The stage varied between Ta and T1. A statistically significant difference was found between the control and the tumor group (LG and HG) for all parameters tested (TL, hTERT, TRF1, TRF2, PARP1 and TANK). No statistically significant difference was found within the tumor group between LG and HG for TRF2. In the biopsies performed on the apparently healthy mucosa of the patients with LG and HG SBC, a statistically significant difference was observed for TBP and hTERT but not for TL. Compared with the control samples, the samples of healthy mucosa of patients with SBC were found to be significantly different for all parameters analyzed. At the cystoscopic follow-up, a total of 11 tumor recurrences were observed: 8 of them in the previous HG (2 at 3 months, 4 at 6 months and 2 at 12 months) and 3 in the LG (2 at 6 months and 1 at 12 months). Regarding the correlation of the parameters tested and tumor recurrence/grading, the Pearson Chi-square test showed a tendency for statistical significance (p<0.06). A significant correlation was observed between TL, hTERT and PARP-1 values and the risk of recurrence (RR). No significant correlation was found between RR and TRF1, TRF2 and TANK. Only TRF1 and TRF2 assessed on samples of healthy mucosa of the tumor group were significantly associated with RR. Discussion: Compared with the control group, the SBC group showed a statistically significant reduction of TL (more evident in HG than in LG tumors), a reduced expression of TRF1 and TRF2, and an overexpression of hTERT, TANK and PARP-1. Significant correlations with SBC grading were demonstrated; HG tumors showed shorter telomeres, lower TRF1 and TRF2 values and higher hTERT, TANK and PARP- 1 values compared to LG tumors. A statistically significant correlation between the RR and grading was also shown. There was an earlier appearance of recurrence in patients with shorter telomeres and higher hTERT and PARP-1 values. No statistically significant correlation was found between the earliness of recurrence and TBP expression. Conclusion: The data of this study allowed us to confirm that TL, and especially its shortening, plays a crucial role in the multistep process of malignant transformation of urothelial cells. This instability appears to be largely influenced by the dysfunction of some TBP and by the permissive role of telomerase reactivation, which, in turn, represents a key moment in cancer cell immortalization.

TELOMERE LENGTH, TELOMERASE ACTIVITY AND TELOMERE-BINDING PROTEINS IN BLADDER CANCER: RELATIONSHIP WITH GRADING AND RECURRENCE

GALI', ALESSANDRO;MUCCIARDI, Massimo;INFERRERA, Antonino;MACCHIONE, LUCIANO;MAGNO, Carlo
2011-01-01

Abstract

Aim: To evaluate the relationship between telomere length (TL), telomerase activity and telomere-binding proteins (TBP) and grading and recurrence rate in patients with superficial bladder cancer (SBC). Patients and Methods: In 35 patients (tumor group; age: 63.9±10.6 years) with SBC, samples from the bladder tumor and disease-free bladder mucosa were obtained. In the control group of 23 healthy individuals (age: 65.3±10.1 years), samples from the bladder mucosa were collected. In all samples, TL was detected by Southern blot, while the expression of hTERT and of several TBP (TRF1, TRF2, PARP1 and TANK) were detected by Western blot. Histological examination was carried out on all samples. The patients underwent immuno- or chemotherapy, and for all of them, cytoscopy was performed at 3, 6 and 12 months. Statistical analysis of the results was performed using the parametric ANOVA test and the post-hoc Bonferroni test. Statistically significant results were considered when p<0.05. Results: The histological examination in the tumor group revealed 15 (42.9%) high-grade (HG) SBC and 20 (57.1%) low-grade (LG) SBC. The stage varied between Ta and T1. A statistically significant difference was found between the control and the tumor group (LG and HG) for all parameters tested (TL, hTERT, TRF1, TRF2, PARP1 and TANK). No statistically significant difference was found within the tumor group between LG and HG for TRF2. In the biopsies performed on the apparently healthy mucosa of the patients with LG and HG SBC, a statistically significant difference was observed for TBP and hTERT but not for TL. Compared with the control samples, the samples of healthy mucosa of patients with SBC were found to be significantly different for all parameters analyzed. At the cystoscopic follow-up, a total of 11 tumor recurrences were observed: 8 of them in the previous HG (2 at 3 months, 4 at 6 months and 2 at 12 months) and 3 in the LG (2 at 6 months and 1 at 12 months). Regarding the correlation of the parameters tested and tumor recurrence/grading, the Pearson Chi-square test showed a tendency for statistical significance (p<0.06). A significant correlation was observed between TL, hTERT and PARP-1 values and the risk of recurrence (RR). No significant correlation was found between RR and TRF1, TRF2 and TANK. Only TRF1 and TRF2 assessed on samples of healthy mucosa of the tumor group were significantly associated with RR. Discussion: Compared with the control group, the SBC group showed a statistically significant reduction of TL (more evident in HG than in LG tumors), a reduced expression of TRF1 and TRF2, and an overexpression of hTERT, TANK and PARP-1. Significant correlations with SBC grading were demonstrated; HG tumors showed shorter telomeres, lower TRF1 and TRF2 values and higher hTERT, TANK and PARP- 1 values compared to LG tumors. A statistically significant correlation between the RR and grading was also shown. There was an earlier appearance of recurrence in patients with shorter telomeres and higher hTERT and PARP-1 values. No statistically significant correlation was found between the earliness of recurrence and TBP expression. Conclusion: The data of this study allowed us to confirm that TL, and especially its shortening, plays a crucial role in the multistep process of malignant transformation of urothelial cells. This instability appears to be largely influenced by the dysfunction of some TBP and by the permissive role of telomerase reactivation, which, in turn, represents a key moment in cancer cell immortalization.
2011
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11570/2391821
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