Tao Yifeng, Lin Feng, Li Ruidong, Shen Jie, Wang Zhengxin
Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
Department of General Surgery, Taizhou First People's Hospital, Taizhou, Zhejiang 318020, China.
Int J Biochem Cell Biol. 2016 Aug;77(Pt A):129-140. doi: 10.1016/j.biocel.2016.05.022. Epub 2016 Jun 13.
Prolyl hydroxylase 2 is a key regulator of hypoxia-inducible factor 1 alpha protein, and has previously been implicated as a tumor suppressor in various cancers. However, the function of prolyl hydroxylase 2 in liver cancer has yet to be elucidated. Characterization of prolyl hydroxylase 2 function and related mechanisms in liver cancer may enable the development of targeted therapy. Here we found that prolyl hydroxylase 2 overexpression in human hepatocellular carcinoma cancer cell lines inhibited cell proliferation, while prolyl hydroxylase 2 knockdown enhanced cell proliferation. Further analyses revealed that the prolyl hydroxylase 2-mediated inhibition of cell proliferation was due to a cell cycle arrest at the G1/S transition. Moreover, the block in cell cycle was facilitated by negative regulation of cyclin D1, a process dependent on the hydroxylase activity of prolyl hydroxylase 2. Using an in vivo xenograft mouse model, we found that the overexpression of prolyl hydroxylase 2 led to a reduction in tumor size. Evaluation of paired human liver cancer patient samples revealed that prolyl hydroxylase 2 protein levels were significantly reduced in 6 of the 10 cancer tissues as compared to their respective normal tissue controls. Furthermore, elevated expression of prolyl hydroxylase 2 was associated with significantly prolonged survival in patients with liver cancer. These results suggest that prolyl hydroxylase 2 plays an important tumor suppressive role in liver cancer and may prove to be of prognostic and therapeutic value.
脯氨酰羟化酶2是缺氧诱导因子1α蛋白的关键调节因子，此前已被认为是多种癌症中的肿瘤抑制因子。然而，脯氨酰羟化酶2在肝癌中的功能尚未阐明。对脯氨酰羟化酶2在肝癌中的功能及相关机制进行表征，可能有助于开发靶向治疗方法。在此，我们发现人肝癌细胞系中脯氨酰羟化酶2的过表达抑制细胞增殖，而脯氨酰羟化酶2的敲低则增强细胞增殖。进一步分析表明，脯氨酰羟化酶2介导的细胞增殖抑制是由于细胞周期在G1/S期转换时停滞。此外，细胞周期的阻滞是由细胞周期蛋白D1的负调控促进的，这一过程依赖于脯氨酰羟化酶2的羟化酶活性。使用体内异种移植小鼠模型，我们发现脯氨酰羟化酶2的过表达导致肿瘤大小减小。对配对的人类肝癌患者样本进行评估发现，与各自的正常组织对照相比，10个癌组织中有6个组织的脯氨酰羟化酶2蛋白水平显著降低。此外，脯氨酰羟化酶2的高表达与肝癌患者的生存期显著延长相关。这些结果表明，脯氨酰羟化酶2在肝癌中发挥重要的肿瘤抑制作用，可能具有预后和治疗价值。
