Liu J Y, Dai Y B, Li X, Cao K, Xie D, Tong Z T, Long Z, Xiao H, Chen M K, Ye Y L, Liu B, Tan J, Tang J, Xu Z Z, Gan Y, Zhou Y H, Deng F, He L Y
Department of Urology, The Third Xiangya Hospital of Central South University, Changsha 410013, China.
Institute of Prostate Disease of Central South University, Changsha 410013, China.
Cell Death Dis. 2017 Mar 23;8(3):e2691. doi: 10.1038/cddis.2017.118.
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.
溶质载体家族12成员5（SLC12A5）是一种整合膜钾氯共转运体，可维持神经元中的氯稳态，其表达异常并参与某些癌症的肿瘤发生。然而，SLC12A5在人膀胱尿路上皮癌（BUC）中的临床意义和生物学作用仍不清楚。在本研究中，使用定量实时逆转录聚合酶链反应（qRT-PCR）、蛋白质印迹和免疫组织化学（IHC）检测了原发性BUC临床标本和BUC细胞系中SLC12A5的表达。对SLC12A5表达的预后价值及其与BUC患者临床病理特征的相关性进行了统计学分析。进行了一系列体外和体内试验，以阐明SLC12A5在BUC中的作用及其潜在机制。目前的结果表明，SLC12A5在BUC组织中的表达显著增加。SLC12A5表达与肿瘤淋巴结转移（TNM）分期显著相关。Kaplan-Meier生存曲线显示，SLC12A5高表达与BUC患者的不良生存相关。多变量分析表明，SLC12A5表达是患者生存的独立预后标志物。SLC12A5的下调在体外抑制了BUC细胞的迁移和侵袭能力，敲低SLC12A5在体内减少了BUC转移。此外，我们发现SLC12A5通过NF-κB依赖性转录增强MMP-7表达来促进BUC细胞迁移和侵袭。综上所述，我们的研究结果表明，SLC12A5可能通过调节NF-κB/MMP-7信号通路在BUC的发生和发展中作为肿瘤转移促进因子发挥作用。因此，SLC12A5可能是BUC的预后标志物和治疗靶点。
