Abstract
Solute carrier family 12 member 5 (SLC12A5), an integral membrane KCl cotransporter, which maintains chloride homeostasis in neurons, is aberrantly expressed and involved in the tumorigenesis of certain cancers. However, the clinical significance and biological role of SLC12A5 in human bladder urothelial carcinoma (BUC) remains unclear. In this study, the expression of SLC12A5 was examined in clinical specimens of primary BUC and in BUC cell lines using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), western blot and immunohistochemistry (IHC). The prognostic value of SLC12A5 expression and its correlation with the clinicopathological features of patients with BUC were analyzed statistically. A series of in vitro and in vivo assays were performed to elucidate the effect of SLC12A5 in BUC and its underlying mechanisms. The present results showed that SLC12A5 expression was significantly increased in BUC tissues. SLC12A5 expression significantly correlated with the tumor node metastasis (TNM) stage. Kaplan–Meier survival curves showed that high SLC12A5 expression was associated with poor survival in patients with BUC. Multivariate analysis indicated that SLC12A5 expression was an independent prognostic marker for the survival of patients. Downregulation of SLC12A5 inhibited the migratory and invasive abilities of BUC cells in vitro, and knocking down SLC12A5 diminished BUC metastasis in vivo. Moreover, we identified that SLC12A5 promoted the migration and invasion of BUC by enhancing MMP-7 expression via NF-κB-dependent transcription. Taken together, our findings indicated that SLC12A5 might function as a tumor metastasis promoting factor in the development and progression of BUC by regulating the NF-κB/MMP-7 signaling pathway. Thus, SLC12A5 might be a prognostic marker as well as a therapeutic target for BUC.
Highlights
Bladder urothelial carcinoma (BUC) is the fourth most common cancer in men, accounting for 7% of all cancer cases
Radical cystectomy (RC) is the cornerstone of the management of invasive BUC and in superficial disease that is at high risk of recurrence and progression.[4]
We found that SLC12A5 mRNA (Figure 1a) and protein (Figure 1b) expression were higher in human BUC tissues than in the paired adjacent nontumor tissues
Summary
Bladder urothelial carcinoma (BUC) is the fourth most common cancer in men, accounting for 7% of all cancer cases. In 2016, there will be 76 960 new cases of BUC in the USA alone, leading to 16 390 cancer-related deaths.[1] Most patients with primary BUC initially present with non-muscle invasive carcinoma, whereas the remaining 20–25% of primary tumors are already muscle invasive at first diagnosis.[2,3] Radical cystectomy (RC) is the cornerstone of the management of invasive BUC and in superficial disease that is at high risk of recurrence and progression.[4] Despite recent developments in therapeutic strategies including surgical resection and chemotherapy, the disease recurs in approximately 50% of patients, and the 5-year overall survival rate is only 6% for patients who develop or present with distant metastatic disease.[1] the high metastasis of BUC after RC surgery has always been the major obstacle to enhancing the survival rate in clinical treatment. Received 15.10.16; revised 21.2.17; accepted 22.2.17; Edited by T Kaufmann to the progression and development of colorectal cancer Despite these extensive investigations in colorectal cancer, the expression, clinical significance and biological function of SLC12A5 in BUC remains poorly understood. The present study was conducted to determine the molecular mechanisms underlying the expression of SLC12A5 and its clinical significance in human BUC
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