晚期糖基化终产物受体部分调节肾透明细胞癌中高迁移率族蛋白B1-细胞外信号调节激酶活化

Receptor for advanced glycation end products partially mediates high.mobility group box-l-extra- cellular signal regulated kinases activation in clear cell renal cell carcinoma

目的观察晚期糖基化终产物受体（RAGE）和高迁移率族蛋白B1柳j胞外信号调节激酶（HMGBl．ERKs）在肾透明细胞癌（CCRCC）发生进展中的作用。方法采用组织芯片技术检测CCRCC中RAGE和HMGBl的表达。HMGBl对静态或RAGE低表达的CCRCC细胞进行干预，Westernblot法检测ERK1／2磷酸化表达。结果CCRCC中RAGE及HMGBl共表达水平升高与患者的临床参数包括肿瘤大小（≤7．00cm，72．4％；〉7．0cm，27．6％）、核Fuhrman分级（G1，8．2％；G2，43．5％；G3，38．3％；G4，10．0％）和临床分期（I期，63．5％；Ⅱ期，13．3％；Ⅲ期，14．1％；Ⅳ期，9．1％）呈正相关（P〈0．05）。在HMGB1潜伏期内ERK1／2活化具有时间和剂量依赖性，其激活可被U0126[丝裂原细胞外激酶（MEK1／2）抑制剂]完全阻断或被RAGE下调部分逆转。结论HMGBl可通过RAGE部分调节而活化ERK1／2，从而促进CCRCC的发生和发展。

Objective To explore the expression of receptor for advanced glycation end products （RAGE） and high-mobility group box-1 （ HMGB1 ） and their role in development and progression of clear cell renal cell carcinoma （CCRCC）. Methods The expression of RAGE and HMGB1 was examined in CCRCC by using tissue microarrays. In vitro, quiescent or RAGE-reduced CCRCC cells were subjected to treatment with HMGB1 and harvested for detecting extracellular signal regulated kinase （ERK1/2） phos- pborylation via Western blotting. Results Elevated co-expression of RAGE and HMGB1 in CCRCC was correlated positively with tumor size （ 〈7.0 cm, 72. 4% ; 〉7.0 era, 27.6% ） , nuclear Fuhrman grade （Gt, 8.2%; G2, 43.5%; G3, 38.3% ; G4, 10.0%） and clinical stage （ Ⅰ , 63.5%; Ⅱ, 13.3% ; Ⅲ, 14. 1%; Ⅳ, 9. 1% ） （P 〈 0. 05）. HMGB1 incubation induced ERK1/2 activation in a time- and dose-dependent manner, which could be completely blocked by U0126 [ mitogen extracellular kinase （MEK） 1/2 inhibitor and partially reversed by RAGE knockdown. Conclusion HMGB1 promotes the development and progression of CCRCC via ERK1/2 activation, which is partially mediated by RAGE.