Expression of p-FOXO3/FOXO3 in bladder cancer and its correlation with clinicopathology and tumor recurrence

Abstract

Background: Survey for more accurate biomarkers for predicting and preventing the future recurrence in high risk patients is urgently needed. The transcription factor forkhead box-O3 (FOXO3) is a well-established tumor suppressor. Its phosphorylation (p-FOXO3) as well as deregulation is involved in cancer initiation, progression and drug resistance. Therefore, we proposed that p-FOXO3/FOXO3 ratio change may play important role in the bladder cancer recurrence.

Methods: Surgical specimens of cancer tissue were obtained from 75 patients with bladder cancer (30 of non-recurrent and 45 of recurrent). The relative expression levels of p-FOXO3/FOXO3 in cancer tissue were measured by immunohistochemistry (IHC) stain and graded according to stain intensity. The correlation p-FOXO3/FOXO3 with clinicopathological parameters and tumor recurrence was analyzed.

Results: For bladder cancer patients with tumor recurrence, higher tumor grade (82% vs 70%, P=0.04) and stage (≥II, 49% vs 33%, P=0.02) in these patients was seen. In IHC study of paired tumor tissues, 39 out of 75 (52%) patients have increased p-FOXO3/FOXO3 ratio and they are closely related to tumor grade (low grade vs high grade =29.4% vs 58.6%, P=0.01) but not related to stage (low stage vs high stage =46.5% vs 59.3%, P=0.26). Regarding to tumor recurrence, the p-FOXO3/FOXO3 ratio is significant higher in recurrent group than non-recurrent group patients (0.78±0.15 vs 1.25±0.11, P=0.03). As comparing the first recurrence and subsequent recurrence group patients, there is no difference in the level of p-FOXO3/FOXO3 ratio (1.25±0.11 vs 1.10±0.09, P=0.25). Interestingly, recurrent tumors in low grade bladder cancer patients have marked increased p-FOXO3/FOXO3 ratio than non-recurrent tumors (0.90±0.22 vs 0.15±0.12, P=0.02).

Conclusion: Increased p-FOXO3/FOXO3 ratio has been observed in bladder cancer patients with tumor recurrence and it is closely related to higher tumor grade. Low grade bladder cancer is high risk in recurrence when p-FOXO3/FOXO3 ratio increased. These results implicated that p-FOXO3/FOXO3 ratio can be applied as a useful marker for further treatment decision making and prognostic of tumor recurrence in bladder cancer patients.

Keywords: Bladder cancer; clinicopathology; p-FOXO3/FOXO3; tumor recurrence.

Figure 1

Immunohistochemistry staining of p-FOXO3 and FOXO3 in non-recurrent and recurrent bladder cancer (HE, ×400).

Figure 2

The distribution of p-FOXO3/FOXO3 ratio among patients with non-recurrent (n=30), primary recurrent (n=45) and their subsequent recurrent bladder cancer tumors. The p-FOXO3/FOXO3 ratio is significant higher in recurrent group than non-recurrent group patients (0.78±0.15 vs 1.25±0.11, P=0.03). As comparing the first recurrence and subsequent recurrence group patients, there is no difference in the level of p-FOXO3/FOXO3 ratio (1.25±0.11 vs 1.10±0.09, P=0.25).

Figure 3

The p-FOXO3/FOXO3 ratio distribution of non-recurrent and recurrent tumors in low grade (n=18) and high grade bladder cancer (n=57). Recurrent tumors in low grade bladder cancer patients have marked increased p-FOXO3/FOXO3 ratio than non-recurrent tumors (0.90±0.22 vs 0.15±0.12, P=0.02) while there is no significant difference among high grade tumors.