Wei Daoyan, Gong Weida, Oh Sang C, Li Qiang, Kim Won Dong, Wang Liwei, Le Xiangdong, Yao James, Wu Tsung T, Huang Suyun, Xie Keping
Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Res. 2005 Jun 1;65(11):4809-16. doi: 10.1158/0008-5472.CAN-04-3741.
Identification of precise prognostic marker and effective therapeutic target is pivotal in the treatment of gastric cancer. In the present study, we determined the level of RUNX3 expression in gastric cancer cells and gastric cancer specimens and the impact of its alteration on cancer biology and clinical outcome. There was a loss or substantial decrease of RUNX3 protein expression in 86 cases of gastric tumors as compared with that in normal gastric mucosa (P < 0.0001), which was significantly associated with inferior survival duration (P = 0.0005). In a Cox proportional hazards model, RUNX3 expression independently predicted better survival (P = 0.036). Moreover, various human gastric cancer cell lines also exhibited loss or drastic decrease of RUNX3 expression. Enforced restoration of RUNX3 expression led to down-regulation of cyclin D1 but to up-regulation of p27, caspase 3, 7, and 8 expression, cell cycle arrest, and apoptosis in vitro, and dramatic attenuation of tumor growth and abrogation of metastasis in animal models. Therefore, we offered both clinical and mechanistic evidence that RUNX3 was an independent prognostic factor and a potential therapeutic target for gastric cancer.
鉴定精确的预后标志物和有效的治疗靶点对胃癌治疗至关重要。在本研究中，我们测定了胃癌细胞和胃癌标本中RUNX3的表达水平，以及其改变对癌症生物学特性和临床结局的影响。与正常胃黏膜相比，86例胃肿瘤中RUNX3蛋白表达缺失或显著降低（P < 0.0001），这与较差的生存时间显著相关（P = 0.0005）。在Cox比例风险模型中，RUNX3表达独立预测更好的生存（P = 0.036）。此外，多种人胃癌细胞系也表现出RUNX3表达缺失或显著降低。在体外，强制恢复RUNX3表达导致细胞周期蛋白D1下调，但p27、半胱天冬酶3、7和8表达上调，细胞周期停滞和凋亡，并在动物模型中显著抑制肿瘤生长和转移。因此，我们提供了临床和机制证据，表明RUNX3是胃癌的独立预后因素和潜在治疗靶点。
