As one of the most common malignancies of the urinary system, Bladder cancer remains with a poor prognosis although some progress has been made in diagnosis and treatment in recent years. Despite several markers have been studied for commercial use in bladder cancer, including bladder tumor antigen (BTA) and NMP-22, more markers are still in the preclinical stage, such as microsatellite analysis, telomerase and survivin (11, 12, 20). Especially on NMP-22 test, as a widely used method, has been shown to be elevated in some benign disease or malignant disease other than bladder can also cause increased NMP-22 levels similar to bladder cancer. Moreover, some studies on NMP-22 have revealed that the overall sensitivity and specificity of NMP-22 are low, which greatly limited its clinical application (21). Therefore, finding better, reliable and non-invasive bladder cancer markers for early diagnosis and postoperative review is a significant topic in urosurgery.
MMPs is a family of metal-dependent extracellular proteases, which are not generally expressed in normal tissues, their production and activity are upregulated during injury, inflammation, and tumorigenesis (22). However,MMP-28 is unlike many traditional MMPs it was also expressed in normal tissues, including the basal and suprabasal keratinocytes of the skin, in developing testicular germ cells, and the lung (15, 18), its overexpression in carcinomas may predict survival in patients such as glioblastoma (23) and gastric cancer (24). In spite of this, MMP-28 and clinicopathological parameters have not been reported in bladder cancer yet.
Up to now, invasion depth, lymph node metastasis and distant metastasis are considered as prognostic factors of bladder cancer. According to our study, we have found that overexpression of MMP-28 was significantly related to poor prognosis of patients with bladder cancer, and MMP-28 was shown to be an independent prognostic. Further analysis showed that the mean survival time of patients with low MMP-28 expression was significantly longer than that of patients with MMP-28 overexpression. It is suggested that MMP-28 can be used as an effective and objective indicator to identify the high-risk group of bladder cancer invasion and progression.
In the present study, immunohistochemistry was adopted to explore the expression of MMP-28 and its relationship with clinicopathological characteristics and prognosis in 491 patients with bladder cancer. Immune reaction scoring results of MMP-28 staining proved that MMP-28 was obviously increasing compared with that in normal bladder tissues, which indicated an important marker role of MMP-28 in bladder cancer. When analyzed the association of MMP-28 staining with clinicopathological and genetic features, we found that positive MMP-28 staining was more likely to be detected in large tumor size, multiple tumors and high histological grade, indicating the more malignant the tumor is in situ, the higher expression of MMP-28. Moreover, it's also strongly correlated with tumor metastasis. In our research, invasion depth, lymph node metastasis, vessel invasion and distant metastasis were also found to be highly expressed. However, MMP-28 expression was not found to be related with patients' age or gender.
As MMP-28 has been found that it can induce epithelial cells to transform into mesenchymal cells and invade cells through TGF-β-dependent mechanism, thus promoting the progress of bladder cancer. Therefore, we analyzed the prognostic value of MMP-28 on the overall survival of bladder cancer patients. Kaplan-Meier analysis revealed a statistically significant correlation between increased MMP-28 expression and poor overall survival in bladder cancer patients, showing that patients with bladder cancer of positive MMP-28 staining had a higher risk of death compared with those with negative MMP-28 staining. Besides, elevated MMP- 28 expression had shorter overall survival time than those with low expression, and the prognostic effect of MMP-28 expression was independent prognostic elements for bladder cancer.