CD147 as a novel biomarker for predicting the prognosis and clinicopathological features of bladder cancer: a meta-analysis

Abstract

Objective: To assess the prognostic and clinicopathological characteristics of CD147 in human bladder cancer.

Methods: Studies on CD147 expression in bladder cancer were retrieved from PubMed, EMBASE, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, and the WanFang databases. Outcomes were pooled with meta-analyzing softwares RevMan 5.3 and STATA 14.0.

Results: Twenty-four studies with 25 datasets demonstrated that CD147 expression was higher in bladder cancer than in non-cancer tissues (OR=43.64, P<0.00001). Moreover, this increase was associated with more advanced clinical stages (OR=73.89, P<0.0001), deeper invasion (OR=3.22, P<0.00001), lower histological differentiation (OR=4.54, P=0.0005), poorer overall survival (univariate analysis, HR=2.63, P<0.00001; multivariate analysis, HR=1.86, P=0.00036), disease specific survival (univariate analysis, HR=1.65, P=0.002), disease recurrence-free survival (univariate analysis, HR=2.78, P=0.001; multivariate analysis, HR=5.51, P=0.017), rate of recurrence (OR=1.91, P=0.0006), invasive depth (pT2∼T4 vs. pTa∼T1; OR=3.22, P<0.00001), and histological differentiation (low versus moderate-to-high; OR=4.54, P=0.0005). No difference was found among disease specific survival in multivariate analysis (P=0.067), lymph node metastasis (P=0.12), and sex (P=0.15).

Conclusion: CD147 could be a biomarker for early diagnosis, treatment, and prognosis of bladder cancer.

Keywords: CD147; bladder cancer; clinicopathological features; meta-analysis; prognosis.

Figure 1. Flowchart of selection of studies for inclusion in meta-analysis

A total of 147 studies were identified, and 63 studies were excluded because of duplication. After reading the titles and abstracts, 50 studies were excluded. 34 possible full text studies were carefully reviewed (animal studies [n = 3]; review and meta-analysis [n = 5]; no control group [n = 2]). Finally, 24 studies were included for quantitative analysis

Figure 2. Forest plots of CD147 expression and survival analysis

The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the study-specific weight (inverse of the variance). The diamonds represent the pooled OR/HR and 95% CI. The solid vertical line is at the null value (OR/HR=1). (A) The relationship between CD147 expression and overall survival (for univariate data; Hedman, T 2015 a: data with neoadjuvant chemotherapy and cystectomy as the therapeutic regimen, Hemdan, T 2015 b: data with only cystectomy as the therapeutic regimen). CD147 expression was associated with overall survival (HR=2.63, 95%CI= [1.96, 3.53], P<0.00001). (B) The relationship between CD147 expression and overall survival (for multivariate data). CD147 expression was associated with overall survival (HR=1.86, 95%CI= [1.32, 2.62], P=0.00036). (C) The relationship between CD147 expression and disease specific survival (for univariate data; Hedman, T 2015 a: data with neoadjuvant chemotherapy and cystectomy as the therapeutic regimen, Hemdan, T 2015 b: data with only cystectomy as the therapeutic regimen). CD147 expression was associated with disease specific survival (HR=1.65, 95%CI= [1.20, 2.27], P=0.002). (D) The relationship between CD147 expression and disease specific survival (for multivariate data). CD147 expression was associated with disease specific survival (HR=1.98, 95%CI= [0.95, 4.12], P=0.067). (E) The relationship between CD147 expression and disease recurrence-free survival (for univariate data). CD147 expression was associated with disease specific survival (HR=2.78, 95%CI= [1.56, 4.99], P=0.001). (F) The relationship between CD147 expression and recurrence. CD147 expression was associated with recurrence (OR=1.91, 95%CI= [1.32, 2.77], P=0.0006).

Figure 3. Forest plots of CD147 expression in different types of bladder tissues

The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the study-specific weight (inverse of the variance). The diamonds represent the pooled OR and 95% CI. The solid vertical line is at the null value (OR=1). (A) CD147 positive expression between bladder cancer tissues and non-cancer bladder tissues. Significant difference was found between two groups (OR=43.64, 95%CI=[23.26, 81.87], P<0.00001). (B) CD147 positive expression between bladder cancer tissues and bladder embryonic tissues. Significant difference was found between two groups (OR=46.78, 95%CI=[6.17, 354.65], P=0.0002). (C) CD147 positive expression between bladder cancer tissues and normal bladder tissues. Significant difference was found between two groups (OR=37.99, 95%CI=[16.97, 85.03], P<0.00001). (D) CD147 positive expression between bladder cancer tissues and para-carcinoma tissues. Significant difference was found between two groups (OR=59.50, 95%CI=[13.75, 257.42], P<0.00001).

Figure 4. Forest plots of CD147 expression and clinicopathological features of bladder cancer patients

The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the study-specific weight (inverse of the variance). The diamonds represent the pooled OR and 95% CI. The solid vertical line is at the null value (OR=1). (A) The relationship between CD147 expression and clinical stage. Significant difference was found between TNM III-IV stage and TNM I-II stage (OR=73.89, 95%CI=[9.61, 568.15], P<0.0001). (B) The relationship between CD147 expression and invasive depth. Significant difference was found between pT2-T4 group and pTa-T1 group (OR=3.22, 95%CI=[1.94, 5.35], P<0.00001). (C) The relationship between CD147 expression and lymph node metastasis. CD147 expression wasn’t associated with lymph node metastasis (OR=2.20, 95%CI=[0.82, 5.89], P=0.12). (D) The relationship between CD147 expression and histological differentiation. CD147 positive expression was associated with low differentiation (OR=4.54, 95%CI=[1.95, 10.58], P=0.0005). (E) The relationship between CD147 expression and gender. CD147 expression wasn’t associated with gender (OR=1.36, 95%CI=[0.90, 2.05], P=0.15).

Figure 5. Sensitivity analysis

We exclude study one by one to evaluate the influences of individual studies on the final effect and all the results were consist with the result of including all studies, which means our results are stable and reliable. (A) CD147 expression and overall survival with univariate analysis; (B) CD147 expression and overall survival with multivariate analysis; (C) CD147 expression and disease specific survival with univariate analysis; (D) CD147 expression and disease specific survival with multivariate analysis; (E) CD147 expression and disease recurrence-free survival with univariate analysis; (F) CD147 expression and recurrence; (G) CD147 positive expression between bladder cancer tissues and non-cancer bladder tissues; (H) CD147 positive expression between bladder cancer tissues and bladder embryonic tissues; (I) CD147 positive expression between bladder cancer tissues and normal bladder tissues; (J) CD147 positive expression between bladder cancer tissues and para-carcinoma tissues; (K) CD147 expression and clinical stage; (L) CD147 expression and invasive depth; (M) CD147 expression and lymph node metastasis; (N) CD147 expression and histological differentiation; (O) CD147 expression and gender.

Figure 6. Publication bias

No publication bias was found by egger’s test except for CD147 positive expression between bladder cancer tissues and normal bladder tissues. (A) CD147 expression and overall survival with univariate analysis; (B) CD147 expression and overall survival with multivariate analysis; (C) CD147 expression and disease specific survival with univariate analysis; (D) CD147 expression and disease specific survival with multivariate analysis; (E) CD147 expression and recurrence; (F) CD147 positive expression between bladder cancer tissues and non-cancer bladder tissues; (G) CD147 positive expression between bladder cancer tissues and normal bladder tissues; (H) CD147 positive expression between bladder cancer tissues and normal bladder tissues (trim and fill method); (I) CD147 expression and invasive depth; (J) CD147 expression and lymph node metastasis; (K): CD147 expression and histological differentiation; (L) CD147 expression and gender.