Liang Xiuming, Zeng Jiping, Wang Lixiang, Shen Li, Li Shuyan, Ma Lin, Ci Xinyu, Yu Jingya, Jia Mutian, Sun Yundong, Liu Zhifang, Liu Shili, Li Wenjuan, Yu Han, Chen Chunyan, Jia Jihui
Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China.
Department of Biochemistry, School of Medicine, Shandong University, Jinan, PR China.
Oncotarget. 2014 Jul 30;5(14):5798-807. doi: 10.18632/oncotarget.2185.
Gastric epithelial cell malignant transformation induced by Helicobactor Pylori contributes to tumor development, but the underlying mechanisms for this remain unclear. Here we demonstrate that RBP2, a newly identified histone demethylase, can be induced by CagA via PI3K/AKT-Sp1 pathway depending on AKT phosphorylation. Sp1 directly binds to RBP2 promoter and enhances its expression then the upregulated RBP2 significantly increases Cyclin D1 transcription, which contributes to gastric epithelial cell malignant transformation. Further data indicate that knockdown of endogenous RBP2 dominantly inhibits gastric cancer (GC) development both in vitro and in vivo. In conclusion, this CagA- PI3K/AKT-Sp1-RBP2-Cyclin D1 pathway may serve as a novel mechanism for gastric epithelial cell malignant transformation and then gastric cancer (GC). Therefore, RBP2 may link chronic inflammation to tumor development and its inhibition may have potential therapeutic advantages.
幽门螺杆菌诱导的胃上皮细胞恶性转化有助于肿瘤发展，但其潜在机制仍不清楚。在此我们证明，一种新发现的组蛋白去甲基化酶RBP2可由CagA通过PI3K/AKT-Sp1途径诱导，这取决于AKT磷酸化。Sp1直接结合RBP2启动子并增强其表达，上调的RBP2随后显著增加细胞周期蛋白D1转录，这有助于胃上皮细胞恶性转化。进一步的数据表明，敲低内源性RBP2在体外和体内均能显著抑制胃癌（GC）的发展。总之，这种CagA-PI3K/AKT-Sp1-RBP2-细胞周期蛋白D1途径可能是胃上皮细胞恶性转化进而导致胃癌（GC）的一种新机制。因此，RBP2可能将慢性炎症与肿瘤发展联系起来，抑制它可能具有潜在的治疗优势。
