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Overexpression of YAP 1 contributes to progressive features and poor prognosis of human urothelial carcinoma of the bladder.

Liu JY, Li YH, Lin HX, Liao YJ, Mai SJ, Liu ZW, Zhang ZL, Jiang LJ, Zhang JX, Kung HF, Zeng YX, Zhou FJ, Xie D - BMC Cancer (2013)

Bottom Line: In univariate survival analysis, a significant association between positive expression of YAP 1 and shortened patients' survival was found (P < 0.001).Importantly, YAP 1 expression (P = 0.003) together with pT and pN status (P< 0.05) provided significant independent prognostic parameters in multivariate analysis.Our findings provide evidences that positive expression of YAP 1 in UCB may be important in the acquisition of an aggressive phenotype, and it is an independent biomarker for poor prognosis of patients with UCB.

View Article: PubMed Central - HTML - PubMed

Affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, No 651, Dongfeng Road East, Guangzhou 510060, China.

ABSTRACT

Background: Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear.

Methods: In this study, the methods of quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting and immunohistochemistry (IHC) were utilized to investigate mRNA/ protein expression of YAP 1 in UCBs. Spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data.

Results: Up-regulated expression of YAP 1 mRNA and protein was observed in the majority of UCBs by qRT-PCR and Western blotting, when compared with their paired normal bladder tissues. By IHC, positive expression of YAP 1 was examined in 113/213 (53.1%) of UCBs and in 6/86 (7.0%) of normal bladder specimens tissues. Positive expression of YAP 1 was correlated with poorer differentiation, higher T classification and higher N classification (P < 0.05). In univariate survival analysis, a significant association between positive expression of YAP 1 and shortened patients' survival was found (P < 0.001). In different subsets of UCB patients, YAP 1 expression was also a prognostic indicator in patients with grade 2 (P = 0.005) or grade 3 (P = 0.046) UCB, and in patients in pT1 (P = 0.013), pT2-4 (P = 0.002), pN- (P < 0.001) or pT2-4/pN- (P = 0.004) stage. Importantly, YAP 1 expression (P = 0.003) together with pT and pN status (P< 0.05) provided significant independent prognostic parameters in multivariate analysis.

Conclusions: Our findings provide evidences that positive expression of YAP 1 in UCB may be important in the acquisition of an aggressive phenotype, and it is an independent biomarker for poor prognosis of patients with UCB.

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Kaplan-Meier survival analysis of YAP 1 expression in patients with UCB (log-rank test). Total, probability of survival of all patients with UCB: negative expression (solid line), n = 100; positive expression (dashed line), n = 113. G1, probability of survival of G1 patients with UCB: negative expression (solid line), n = 49; positive expression (dashed line), n = 28. G2, probability of survival of G2 patients with UCB: negative expression (solid line), n = 29; positive expression (dashed line), n = 40. G3, probability of survival of G3 patients with UCB: negative expression (solid line), n = 22; positive expression (dashed line), n = 45. pTa/pTis, probability of survival of pTa/pTis patients with UCB: negative expression (solid line), n = 52; positive expression (dashed line), n = 37. pT1, probability of survival of pT1 patients with UCB: negative expression (solid line), n = 19; positive expression (dashed line), n = 23. pT2-4, probability of survival of pT2-4 patients with UCB: negative expression (solid line), n = 29; positive expression (dashed line), n = 53. pT2-4/pN-, probability of survival of pT2-4/pN- patients with UCB: negative expression (solid line), n = 25; positive expression (dashed line), n = 39. pN-, probability of survival of pN- patients with UCB: ngative expression (solid line), n = 96; positive expression (dashed line), n = 99. pN+, probability of survival of pN+ patients with UCB: negative expression (solid line), n = 4; positive expression (dashed line), n = 14.
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Figure 2: Kaplan-Meier survival analysis of YAP 1 expression in patients with UCB (log-rank test). Total, probability of survival of all patients with UCB: negative expression (solid line), n = 100; positive expression (dashed line), n = 113. G1, probability of survival of G1 patients with UCB: negative expression (solid line), n = 49; positive expression (dashed line), n = 28. G2, probability of survival of G2 patients with UCB: negative expression (solid line), n = 29; positive expression (dashed line), n = 40. G3, probability of survival of G3 patients with UCB: negative expression (solid line), n = 22; positive expression (dashed line), n = 45. pTa/pTis, probability of survival of pTa/pTis patients with UCB: negative expression (solid line), n = 52; positive expression (dashed line), n = 37. pT1, probability of survival of pT1 patients with UCB: negative expression (solid line), n = 19; positive expression (dashed line), n = 23. pT2-4, probability of survival of pT2-4 patients with UCB: negative expression (solid line), n = 29; positive expression (dashed line), n = 53. pT2-4/pN-, probability of survival of pT2-4/pN- patients with UCB: negative expression (solid line), n = 25; positive expression (dashed line), n = 39. pN-, probability of survival of pN- patients with UCB: ngative expression (solid line), n = 96; positive expression (dashed line), n = 99. pN+, probability of survival of pN+ patients with UCB: negative expression (solid line), n = 4; positive expression (dashed line), n = 14.

Mentions: In univariate survival analyses, cumulative survival curves were calculated according to the Kaplan-Meier method. Differences in survival times were assessed using the log-rank test. First, to confirm the representativeness of the UCBs in our study, we analyzed established prognostic predictors of patient survival. Kaplan-Meier analysis demonstrated a significant impact of well-known clinical pathological prognostic parameters, such as tumor grade, pT status and pN status on patient survival (P < 0.05, Table 2). Assessment of survival in total UCBs revealed that positive expression of YAP 1 was correlated with adverse survival of UCB patients (P < 0.001, Table 2, Figure 2). Moreover, expression of YAP 1 was found to be a prognostic factor in UCB patients having grades 2 and 3 tumors (P = 0.005 and 0.046, respectively, Figure 2, Table 2), pT1 (P = 0.013), pT2-4 (P = 0.002) and pN- (P < 0.001) (Figure 2, Table 2). In addition, survival analysis with regard to YAP 1 expression and a subset of pT2-4 UCB patients without lymph node metastasis (pT2-4/pN-, n = 64) showed that expression of YAP1 was also a significant prognostic factor (P = 0.004, Figure 2, Table 2).


Overexpression of YAP 1 contributes to progressive features and poor prognosis of human urothelial carcinoma of the bladder.

Liu JY, Li YH, Lin HX, Liao YJ, Mai SJ, Liu ZW, Zhang ZL, Jiang LJ, Zhang JX, Kung HF, Zeng YX, Zhou FJ, Xie D - BMC Cancer (2013)

Kaplan-Meier survival analysis of YAP 1 expression in patients with UCB (log-rank test). Total, probability of survival of all patients with UCB: negative expression (solid line), n = 100; positive expression (dashed line), n = 113. G1, probability of survival of G1 patients with UCB: negative expression (solid line), n = 49; positive expression (dashed line), n = 28. G2, probability of survival of G2 patients with UCB: negative expression (solid line), n = 29; positive expression (dashed line), n = 40. G3, probability of survival of G3 patients with UCB: negative expression (solid line), n = 22; positive expression (dashed line), n = 45. pTa/pTis, probability of survival of pTa/pTis patients with UCB: negative expression (solid line), n = 52; positive expression (dashed line), n = 37. pT1, probability of survival of pT1 patients with UCB: negative expression (solid line), n = 19; positive expression (dashed line), n = 23. pT2-4, probability of survival of pT2-4 patients with UCB: negative expression (solid line), n = 29; positive expression (dashed line), n = 53. pT2-4/pN-, probability of survival of pT2-4/pN- patients with UCB: negative expression (solid line), n = 25; positive expression (dashed line), n = 39. pN-, probability of survival of pN- patients with UCB: ngative expression (solid line), n = 96; positive expression (dashed line), n = 99. pN+, probability of survival of pN+ patients with UCB: negative expression (solid line), n = 4; positive expression (dashed line), n = 14.
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Related In: Results  -  Collection

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Figure 2: Kaplan-Meier survival analysis of YAP 1 expression in patients with UCB (log-rank test). Total, probability of survival of all patients with UCB: negative expression (solid line), n = 100; positive expression (dashed line), n = 113. G1, probability of survival of G1 patients with UCB: negative expression (solid line), n = 49; positive expression (dashed line), n = 28. G2, probability of survival of G2 patients with UCB: negative expression (solid line), n = 29; positive expression (dashed line), n = 40. G3, probability of survival of G3 patients with UCB: negative expression (solid line), n = 22; positive expression (dashed line), n = 45. pTa/pTis, probability of survival of pTa/pTis patients with UCB: negative expression (solid line), n = 52; positive expression (dashed line), n = 37. pT1, probability of survival of pT1 patients with UCB: negative expression (solid line), n = 19; positive expression (dashed line), n = 23. pT2-4, probability of survival of pT2-4 patients with UCB: negative expression (solid line), n = 29; positive expression (dashed line), n = 53. pT2-4/pN-, probability of survival of pT2-4/pN- patients with UCB: negative expression (solid line), n = 25; positive expression (dashed line), n = 39. pN-, probability of survival of pN- patients with UCB: ngative expression (solid line), n = 96; positive expression (dashed line), n = 99. pN+, probability of survival of pN+ patients with UCB: negative expression (solid line), n = 4; positive expression (dashed line), n = 14.
Mentions: In univariate survival analyses, cumulative survival curves were calculated according to the Kaplan-Meier method. Differences in survival times were assessed using the log-rank test. First, to confirm the representativeness of the UCBs in our study, we analyzed established prognostic predictors of patient survival. Kaplan-Meier analysis demonstrated a significant impact of well-known clinical pathological prognostic parameters, such as tumor grade, pT status and pN status on patient survival (P < 0.05, Table 2). Assessment of survival in total UCBs revealed that positive expression of YAP 1 was correlated with adverse survival of UCB patients (P < 0.001, Table 2, Figure 2). Moreover, expression of YAP 1 was found to be a prognostic factor in UCB patients having grades 2 and 3 tumors (P = 0.005 and 0.046, respectively, Figure 2, Table 2), pT1 (P = 0.013), pT2-4 (P = 0.002) and pN- (P < 0.001) (Figure 2, Table 2). In addition, survival analysis with regard to YAP 1 expression and a subset of pT2-4 UCB patients without lymph node metastasis (pT2-4/pN-, n = 64) showed that expression of YAP1 was also a significant prognostic factor (P = 0.004, Figure 2, Table 2).

Bottom Line: In univariate survival analysis, a significant association between positive expression of YAP 1 and shortened patients' survival was found (P < 0.001).Importantly, YAP 1 expression (P = 0.003) together with pT and pN status (P< 0.05) provided significant independent prognostic parameters in multivariate analysis.Our findings provide evidences that positive expression of YAP 1 in UCB may be important in the acquisition of an aggressive phenotype, and it is an independent biomarker for poor prognosis of patients with UCB.

View Article: PubMed Central - HTML - PubMed

Affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, No 651, Dongfeng Road East, Guangzhou 510060, China.

ABSTRACT

Background: Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear.

Methods: In this study, the methods of quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting and immunohistochemistry (IHC) were utilized to investigate mRNA/ protein expression of YAP 1 in UCBs. Spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data.

Results: Up-regulated expression of YAP 1 mRNA and protein was observed in the majority of UCBs by qRT-PCR and Western blotting, when compared with their paired normal bladder tissues. By IHC, positive expression of YAP 1 was examined in 113/213 (53.1%) of UCBs and in 6/86 (7.0%) of normal bladder specimens tissues. Positive expression of YAP 1 was correlated with poorer differentiation, higher T classification and higher N classification (P < 0.05). In univariate survival analysis, a significant association between positive expression of YAP 1 and shortened patients' survival was found (P < 0.001). In different subsets of UCB patients, YAP 1 expression was also a prognostic indicator in patients with grade 2 (P = 0.005) or grade 3 (P = 0.046) UCB, and in patients in pT1 (P = 0.013), pT2-4 (P = 0.002), pN- (P < 0.001) or pT2-4/pN- (P = 0.004) stage. Importantly, YAP 1 expression (P = 0.003) together with pT and pN status (P< 0.05) provided significant independent prognostic parameters in multivariate analysis.

Conclusions: Our findings provide evidences that positive expression of YAP 1 in UCB may be important in the acquisition of an aggressive phenotype, and it is an independent biomarker for poor prognosis of patients with UCB.

Show MeSH
Related in: MedlinePlus