Cui Lei, Qu Jianguo, Dang Shengchun, Mao Zhengfa, Wang Xuqing, Fan Xin, Sun Kang, Zhang Jianxin
General Surgery Department, Affiliated Hospital of Jiangsu University, Zhenjiang City, Jiangsu Province, China.
Mol Carcinog. 2014 Sep;53(9):736-43. doi: 10.1002/mc.22025. Epub 2013 Mar 26.
Gastric cancer is one of the most common malignancies and the second leading cause of cancer-related death in the world, and it is very urgent to develop novel therapeutic strategies. Although HIF-1α is the most highly characterized target of prolyl hydroxylase 3 (PHD3), PHD3 has been shown to regulate several signal pathways independent of HIF-1α. Here, we found that the expression of PHD3 was decreased in the clinical gastric cancer samples and reversely correlated with tumor size and tumor stage. Over-expression of PHD3 in the gastric cancer cells significantly inhibited cell growth in vitro and in vivo, while knockdown the expression of PHD3 promoted the tumorigenecity of gastric cancer cells. Mechanistically, it showed that PHD3 downregulated the expression of beta-catenin and inhibited beta-catenin/T-cell factor (TCF) signaling. Taken together, our findings demonstrate that PHD3 inhibits gastric cancer by suppressing the beta-catenin/TCF signaling and PHD3 might be an important therapeutic target in gastric cancer.
胃癌是世界上最常见的恶性肿瘤之一，也是癌症相关死亡的第二大主要原因，因此开发新的治疗策略迫在眉睫。虽然缺氧诱导因子-1α（HIF-1α）是脯氨酰羟化酶3（PHD3）最具特征的靶点，但已证明PHD3可独立于HIF-1α调节多种信号通路。在此，我们发现临床胃癌样本中PHD3的表达降低，且与肿瘤大小和肿瘤分期呈负相关。在胃癌细胞中过表达PHD3可显著抑制体外和体内细胞生长，而敲低PHD3的表达则促进胃癌细胞的致瘤性。机制上，结果表明PHD3下调β-连环蛋白的表达并抑制β-连环蛋白/T细胞因子（TCF）信号传导。综上所述，我们的研究结果表明，PHD3通过抑制β-连环蛋白/TCF信号传导来抑制胃癌，并且PHD3可能是胃癌的一个重要治疗靶点。
