Xu Yue-Mei, Wang Hong-Jiang, Chen Fang, Guo Wan-Hua, Wang Yan-Yang, Li Hang-Yu, Tang Jin-Hai, Ding Ying, Shen Ya-Chen, Li Min, Xuan Wen-Ying, Liu Lin-Hui, Wang Jia, Wang Xue-Rong, Gao Ze-Jun, Liang Xiu-Bin, Su Dong-Ming
State Key Laboratory of Reproductive Medicine, Department of Pathology, Nanjing Medical University, Nanjing, China.
Department of Breast Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Oncotarget. 2015 Dec 15;6(40):42854-67. doi: 10.18632/oncotarget.5733.
HRD1 (3-hydroxy-3-methylglutaryl reductase degradation) is an E3 ubiquitin ligase. We found that HRD1 was significantly downregulated in 170 breast cancer tissues. Low tumoral HRD1 expression was correlated with clinicopathological characteristics and a shorter survival in breast cancer patients. P65 specifically bound to the HRD1 promoter and inhibited HRD1 expression. Suppression of NF-κB activity reversed IL-6-induced downregulation of HRD1 expression. HRD1 interacted with IGF-1R and promoted its ubiquitination and degradation by the proteasome. Overexpression of HRD1 resulted in the inhibition of growth, migration and invasion of breast cancer cells in vitro and in vivo. Furthermore, HRD1 attenuated IL-6-induced epithelial-mesenchymal transition in MCF10A cells. These findings uncover a novel role for HRD1 in breast cancer.
HRD1（3-羟基-3-甲基戊二酰辅酶A还原酶降解蛋白）是一种E3泛素连接酶。我们发现，在170例乳腺癌组织中HRD1显著下调。肿瘤组织中HRD1低表达与乳腺癌患者的临床病理特征及较短生存期相关。P65特异性结合HRD1启动子并抑制HRD1表达。抑制NF-κB活性可逆转IL-6诱导的HRD1表达下调。HRD1与胰岛素样生长因子-1受体（IGF-1R）相互作用，并促进其经蛋白酶体进行泛素化和降解。HRD1过表达导致体外和体内乳腺癌细胞的生长、迁移和侵袭受到抑制。此外，HRD1减弱了IL-6诱导的MCF10A细胞上皮-间质转化。这些发现揭示了HRD1在乳腺癌中的新作用。
