Characteristics of the included literatures
A total of 663 studies were searched and identified (Figure 1), including 119 from Pubmed, 301 from Embase, 20 from CNKI, 15 from Wanfang database, 4 from Cochrane Library, 120 from Google Scholar, 80 from Web of Science and 4 from Clinicaltrial.gov. Next, 252 studies were excluded for duplication. The rest of studies were carefully examined on Title, Abstract, and Key words, and 357 were excluded because they do not match the subject of this meta-analysis. The full text of remaining 54 studies were carefully reviewed and 33 of them were excluded as animal or cell studies (n=18), case report, review, meta-analysis (n=7), and insufficient data from original studies (n=8). As a result, 21 studies were included for the quality evaluation through the Newcastle-Ottawa scale (NOS). The details of the included studies and the NOS score of each study were shown in Tables 1 and 2.
Osteopontin expression and overall survival
In the overall survival analysis, three univariate studies and three multivariate studies were analyzed separately. The univariate studies had no heterogeneity (p=0.981, I2=0%), so a fixed-effects model was used and showed that the OPN positive group had a lower overall survival than the negative group (HR=2.32, 95%CI [1.74, 3.10], p<0.05). Besides, the multivariate studies also had no heterogeneity (p=0.682, I2=0%), so the fixed-effects model was used and presented the same result (HR=2.41, 95%CI [1.63, 3.57], p<0.05) (Figure 2A). In conclusion, the positive expression of OPN is not conducive to the overall survival in prostate cancer patients.
Osteopontin expression and biochemical relapse-free survival
Biochemical relapse of prostate cancer stands for the re-elevation of PSA level in prostate cancer patients underwent clinical therapy. A total of three studies, including 4 univariate analyses and 4 multivariate analyses, were selected for evaluating the association of OPN expression and biochemical relapse-free survival. The univariate studies had a high heterogeneity (p=0.010, I2=78.5%), so the random-effects model was used and showed that the OPN positive group had a lower biochemical relapse-free survival than the negative group (HR=1.42, 95%CI [0.92, 2.17], p<0.05). Sensitivity analysis showed that the result was stable. In addition, the multivariate studies had no heterogeneity (p=0.469, I2=0%), so the fixed-effects model was used and the same result (HR=1.61, 95%CI [1.39, 1.87], p<0.05) was observed (Figure 2B).
Osteopontin expression and other survival studies
Except the overall survival and biochemical relapse-free survival analyses, some studies also mentioned the OPN expression with distant metastasis-free survival, progression-free survival, and disease-specific survival. Although these studies all showed that OPN positive group had a lower survival rate (Figure 2C), respectively, the results were not conclusive in our meta-analysis due to the lack of relevant studies.
Osteopontin expression between prostate cancer tissues and normal prostate tissues
A total of 5 studies reported the expression of OPN between prostate cancer tissues and normal prostate tissues, including 271 prostate cancer tissue samples and 132 normal prostate tissue samples. The heterogeneity of the obtained results is low (p=0.25, I2=26%), so the fixed-effects model is adopted and showed that the expression of OPN in prostate cancer tissues was significantly higher than that in normal prostate cancer tissues (OR=46.55, 95%CI [12.85, 168.59], p<0.00001) (Figure 3A). Then, we performed the sensitivity analysis on the obtained results and excluded individual studies one by one. The heterogeneity did not change significantly, which proves that our conclusion was stable and reliable (Figure 5A). In summary, there was higher expression level of OPN in prostate cancer tissues than in normal prostate tissues.
Osteopontin expression between prostate cancer tissues and benign prostatic hyperplasia
A total of 9 studies reported the comparison of OPN expression in patients with prostate cancer (PCA) and benign prostatic hyperplasia (BPH), including 469 PCA tissue samples and 263 BPH tissue samples. The results obtained from the analysis had a high heterogeneity (p<0.00001, I2=81%), so the random-effects model was adopted. To further determine the stability and reliability of the results, we performed a sensitivity analysis of the included literatures to determine whether individual studies would have an impact on the results. And we found that the heterogeneity decreased after excluding the study of Tozawa[18], with the conclusion that there was higher expression level of OPN in PCA tissues than in BPH tissues (OR=11.07, 95%CI [3.43, 35.75], p<0.0001). The result was stable and acceptable (Figure 5B). In summary, the expression of OPN in PCA tissues was higher than in BPH tissues (Figure 3B).
Osteopontin expression with the Gleason score of prostate cancer
Gleason score is a widely used histological scoring system in prostate cancer, which is associated with the prognosis and biological behavior. A total of 9 studies reported the relationship between OPN expression and the Gleason score of PCA tissues, including 148 high Gleason score samples (>8) and 282 low Gleason score samples (≤7). The result had no heterogeneity (p=0.88, I2=0%), and the fixed-effects model was adopted (Figure 4A). The studies of Forootan and Tilli found that all the prostate cancer tissues were positively stained with OPN, and they compared the Gleason score to the staining intensity of OPN. Although all prostate cancer tissues were positive for OPN staining from their studies, the prostate cancer tissues with high Gleason score had a stronger staining when compared with the low Gleason score tissues. In conclusion, the expression level of OPN was positively correlated with the Gleason score of prostate cancer (OR=2.64, 95%CI [1.49, 4.70], p=0.0009).
Osteopontin expression with the clinical TNM stage of prostate cancer
A total of 4 studies included the relationship between osteopontin and the clinical TNM stage of prostate cancer, among which 93 T III-IV stage patients and 155 T I-II stage patients were reported. The results had no heterogeneity (p=0.49, I2=0%), and the fixed-effects model was adopted (Figure 4B). Overall, the expression level of OPN in T III-IV stage was higher than that in T I-II stage of prostate cancer patients (OR=3.15, 95%CI [1.60, 6.20], p=0.0009).
Osteopontin expression with the Whitmore-Jewett stage of prostate cancer
Whitmore-Jewett stage is the most common staging strategery in clinical practice. This staging method divides prostate cancer into 4 stages (A, B, C, D) according to the degrees of infiltration. A total of 4 studies reported the relationship between osteopontin and the Whitmore-Jewett stage of prostate cancer, including 89 stage C+D patients and 130 stage A+B patients. The results had a low heterogeneity (p=0.19, I2=38%), and the fixed-effects model was used (Figure 4C). When we conducted the sensitivity analysis and excluded the studies in turn, we found that the heterogeneity did not change significantly, so the analysis results were stable. Over all, the expression level of OPN in Whitmore-Jewett stage C+D patients was higher than in stage A+B patients (OR=2.53, 95%CI [1.06, 6.03], p=0.04).
Osteopontin expression with the differentiation of prostate cancer
A total of 6 studies reported the relationship between osteopontin and the differentiation of prostate cancer, including 233 low differentiation samples and 124 high differentiation samples. The results had a significant heterogeneity (p<0.00001, I2=87%), so the random-effects model was adopted and showed that the expression of OPN had no difference between high and low differentiation of prostate cancer tissues (OR=1.79, 95%CI [0.39, 8.33], p=0.46) (Figure 4D). Then we conducted a sensitivity analysis, and after removing each study one by one, the heterogeneity remained constant, which proved that our results were reliable. In conclusion, there was no significant correlation between the expression level of OPN with the differentiation of prostate cancer.
Osteopontin expression with the lymph node metastasis of prostate cancer
Lymph node metastasis of tumors is often associated with poor prognosis, so the early diagnosis and judgment of lymph node metastasis is essential. A total of 4 studies included the relationship between the OPN and lymph node metastasis of prostate cancer, including 290 prostate cancer tissues. The result had a low heterogeneity (p=0.16, I2=42%), so the fixed-effects model was adopted, and showed that the expression of OPN was positively correlated with lymph node metastasis of prostate cancer (OR=3.69, 95%CI [1.88, 7.23], p=0.0001) (Figure 4E). Sensitivity analysis showed the result was stable.
Osteopontin with the distant metastasis of prostate cancer
Distant metastasis including bone or organ metastasis are the most common forms of metastasis in patients with prostate cancer and usually bring a poor prognosis. Three articles including 198 patients have reported the correlation between prostate cancer distant metastasis and OPN. The results had no heterogeneity (p=0.44, I2=0%), so the fixed-effects model was adopted, and showed that the expression of OPN was positively correlated with distant metastasis of prostate cancer (OR=8.10, 95%CI [2.94, 22.35], p=0.01) (Figure 4F). Sensitivity analysis showed that the result was stable.
Publication bias
After analyzing all the results, we examined whether there was publication bias in the included literatures by using Begg’s test, and the conclusions showed that there was no significant publication bias in each analysis (Figure 6), so the results were reliable and stable. Besides, we also conducted the risk of bias summary diagram to show the source of potential bias (Figure 7).