Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
Mol Med Rep. 2017 Dec;16(6):8335-8344. doi: 10.3892/mmr.2017.7637. Epub 2017 Sep 27.
Previous studies have indicated that high expression of lactate dehydrogenase A (LDHA) exists in many human cancers. Recently, several reports showed that silencing or inhibition of LDHA could suppress metastasis of human cancer including renal cell carcinoma (RCC). However, the mechanism remains unknown. The role of LDHA in RCC migration and invasion was investigated using immunohistochemistry, western blotting, Transwell and scratch assays, and in vivo experiment. The influence of LDHA on the Warburg effect was also investigated by LDHA activity and lactate production assay. LDHA was overexpressed in RCC tissues and predicted a worse survival following renal resection. Correlation analysis demonstrated that LDHA was negatively correlated with E‑cadherin and positively with N‑cadherin. Experimentally, both in vivo and in vitro experiments found downregulation of LDHA suppressed RCC cells migration and invasion by inhibiting EMT. In addition, results indicated LDHA could promote the Warburg effect. Further research presented that the LDHA inhibitor, oxamate, suppressed tumor metastasis by inhibiting LDHA activity and EMT. These results demonstrated that LDHA mediates tumor metastasis by promoting EMT in RCC, suggesting that LDHA could be a promising therapeutic target for RCC therapy.
先前的研究表明，许多人类癌症中存在乳酸脱氢酶 A（LDHA）的高表达。最近，有几项报告表明，沉默或抑制 LDHA 可以抑制包括肾细胞癌（RCC）在内的人类癌症的转移。然而，其机制尚不清楚。本研究通过免疫组织化学、Western blot、Transwell 和划痕实验以及体内实验，研究了 LDHA 在 RCC 迁移和侵袭中的作用。通过 LDHA 活性和乳酸产生测定，还研究了 LDHA 对瓦博格效应的影响。LDHA 在 RCC 组织中过表达，并预测肾切除术后生存预后不良。相关性分析表明，LDHA 与 E-钙黏蛋白呈负相关，与 N-钙黏蛋白呈正相关。实验发现，体内和体外实验均发现下调 LDHA 通过抑制 EMT 抑制 RCC 细胞迁移和侵袭。此外，结果表明 LDHA 可以促进瓦博格效应。进一步的研究表明，LDHA 抑制剂 oxamate 通过抑制 LDHA 活性和 EMT 抑制肿瘤转移。这些结果表明，LDHA 通过促进 EMT 介导 RCC 中的肿瘤转移，提示 LDHA 可能成为 RCC 治疗的有前途的治疗靶点。
