The prognostic role of p53 and its correlation with CDK9 in urothelial carcinoma

Abstract

Purpose: The mutation of p53 is considered a pivotal step in bladder cancer pathogenesis. Recently, distinct interactions between p53 and CDK9, a transcription regulator, have been described. In this work, we explored the prognostic role of p53 expression and evaluated its associations with CDK9 in urothelial carcinoma.

Materials and methods: The research group consisted of 67 bladder cancer samples and 32 normal urothelial mucosa samples. All specimens were analyzed using ImageJ and the IHC profiler plugin. To validate the results, 406 cases from The Cancer Genome Atlas database were analyzed.

Results: P53 and CDK9 are overexpressed in urothelial cancer tissues when compared to normal urothelial tissues (p < 0.05). High p53 expression was observed in metastatic tumors and tumors with high CDK9 expression (p < 0,05). High p53 expression was predictive for shorter survival in patients with non-muscle-invasive bladder cancer (HR = 0.107 [0.012-0.96]; p = 0.046) but did not correlate with prognosis in the muscle-invasive group. In high CDK9 cancers, high p53 expression correlated with the occurrence of high-grade and muscle-invasive tumors (p < 0.05).

Conclusion: High expression of p53 correlates with unfavorable clinical features of bladder cancer. CDK9 is associated with the expression of p53, possibly through interactions with p53 inhibitors. Since the blockade of CDK9 in other malignancies reactivates wild-p53 activity, confirming the crosstalk between p53 and CDK9 in bladder cancer may be another step to explain the mechanism of tumor progression in its early stages.

Keywords: Bladder cancer; CDK9; Expression; P53; Prognosis.

Fig. 1

Representative cross-sectional staining patterns of 1a bladder cancer with high p53 expression; 1b bladder cancer with high CDK9 expression; 2a bladder cancer with low p53 expression; 2b bladder cancer with low CDK9 expression; 3a normal mucosa with low p53 expression; 3b normal mucosa with high CDK9 expression and positive reaction in the cells of the stromal inflammatory infiltration; 4a p53 negative control; 4b CDK9 negative control

Fig. 2

P53 expression: a cancer vs. control (p = 0.00001), b T1 and T2–T4 vs. control (p = 0.0001), c in non-metastatic cancers vs. cancers with distant metastasis (M0 vs M1; p = 0.02)

Fig. 3

P53 expression in high CDK9 urothelial cancers depending on: a tumor grade (p = 0.02), b tumor invasiveness (p = 0.037) MIBC muscle-invasive bladder cancer, NMIBC non-muscle-invasive bladder cancer

Fig. 4

Statistically significant results of the TCGA cohort analysis: a TP53 expression in the TCGA cohort depending on the status of lymph node invasion (p = 0.012), b CDK9 expression depending on the presence of TP53 mutation (p = 0.012)