Prolyl hydroxylase-2 inhibits liver tumor cell proliferation and cyclin D1 expression in a hydroxylase-dependent manner.
Prolyl hydroxylase-2 inhibits liver tumor cell proliferation and cyclin D1 expression in a hydroxylase-dependent manner.
复制标题
DOI：
10.1016/j.biocel.2016.05.022
复制
发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Yifeng Tao;F. Lin;Rui‐dong Li;Jie Shen;Zhengxin Wang
中科院分区：
文献类型：
--
作者：
Yifeng Tao;F. Lin;Rui‐dong Li;Jie Shen;Zhengxin Wang
Pro羟基酶2是低氧诱导因子1α蛋白的关键调节因子，此前已被认为是多种癌症的肿瘤抑制因子。然而，Pro-羟基酶2在肝癌中的作用尚不清楚。研究肝癌中脯氨酸羟基酶2的功能及其相关机制可能有助于靶向治疗的发展。在此，我们发现在人肝癌细胞系中过表达的Pro-羟基酶2抑制了细胞的增殖，而Pro-羟基酶2基因敲除则促进了细胞的增殖。进一步的分析表明，Pro-羟基酶2对细胞增殖的抑制是由于细胞周期停滞在G1/S过渡期所致。此外，细胞周期的阻断是由细胞周期蛋白D1的负调控促进的，这一过程依赖于Pro羟基酶2的羟基酶活性。使用体内异种移植小鼠模型，我们发现Pro羟基酶2的过表达导致了肿瘤的缩小。对配对的人类肝癌患者样本的评估显示，与各自的正常组织对照相比，10个癌症组织中有6个组织的Pro-羟基酶2蛋白水平显著降低。此外，Pro-羟基酶2的表达升高与肝癌患者的生存期显著延长有关。这些结果表明，Pro-羟基酶2在肝癌中起着重要的肿瘤抑制作用，并可能被证明具有预后和治疗价值。
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.