Prolyl hydroxylase domain protein 3 and asparaginyl hydroxylase factor inhibiting HIF-1 levels are predictive of tumoral behavior and prognosis in hepatocellular carcinoma.
Prolyl hydroxylase domain protein 3 and asparaginyl hydroxylase factor inhibiting HIF-1 levels are predictive of tumoral behavior and prognosis in hepatocellular carcinoma.
复制标题
脯氨酰羟化酶结构域蛋白 3 和天冬酰胺酰羟化酶因子抑制 HIF-1 水平可预测肝细胞癌的肿瘤行为和预后。
DOI：
10.18632/oncotarget.14677
复制
发表时间：
2017-02-21
期刊：
影响因子：
--
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Ma M;Hua S;Li G;Wang S;Cheng X;He S;Wu P;Chen X
低氧诱导因子(HIF)是氧稳态的关键调节因子。其稳定性和活性受脯氨酸羟基酶结构域(PHD)-1、-2、-3和HIF抑制因子(FIH)的调节。本研究探讨这些氧感受器与肝细胞癌临床行为及预后的关系。肿瘤组织和癌旁肝组织的组织芯片和RT-PCR分析表明，肿瘤内PHD3和FIH的mRNA和蛋白水平均较低。PHD3在肿瘤中的低表达与肿瘤大小、肿瘤包膜不完整、血管侵犯和Ki-67LI升高有关(p<；0.05)。FIH在肿瘤中的低表达与肿瘤包膜不完整、血管侵犯、TNM分期、BCLC分期、微血管密度和Ki-67LI有关(p<；0.05)。PHD3或FIH表达降低的患者无病生存期(DFS)明显缩短，总生存期(OS)降低，复发率高(p<；0.05)，尤其是早期复发。PHD3和FIH表达同时降低的患者肿瘤包膜形成的几率最小，肿瘤的TNM分期最高(p<；0.0083)，OS最低，复发率最高(p<；0.05)。多因素分析显示，FIH低表达独立地预示着肝细胞癌预后不良。这些发现表明，PHD3和FIH在肝细胞癌中的下调与更具侵袭性的肿瘤行为和不良预后有关。PHD3和FIH可能是治疗肝癌的潜在靶点。
Hypoxia-inducible factors (HIFs) are key regulators in oxygen homeostasis. Their stabilization and activity are regulated by prolyl hydroxylase domain (PHD)-1, -2, -3 and factor inhibiting HIF (FIH). This study investigated the relation between these oxygen sensors and the clinical behaviors and prognosis of hepatocellular carcinoma (HCC). Tissue microarray and RT-PCR analysis of tumor tissues and adjacent non-tumor liver tissues revealed that mRNA and protein levels of both PHD3 and FIH were lower within tumors. The lower expression of PHD3 in tumor was associated with larger tumor size, incomplete tumor encapsulation, vascular invasion and higher Ki-67 LI (p < 0.05). The lower expression of FIH in tumor was associated with incomplete tumor encapsulation, vascular invasion, as well as higher TNM stage, BCLC stage, microvascular density and Ki-67 LI (p < 0.05). Patients with reduced expression of PHD3 or FIH had markedly shorter disease-free survival (DFS), lower overall survival (OS), or higher recurrence (p < 0.05), especially early recurrence. Patients with simultaneously reduced expression of PHD3 and FIH exhibited the least chance of forming tumor encapsulation, highest TNM stage (p < 0.0083), lowest OS and highest recurrence rate (p < 0.05). Multivariate analysis indicated that a lower expression of FIH independently predicted a poor prognosis in HCC. These findings indicate that downregulation of PHD3 and FIH in HCC is associated with more aggressive tumor behavior and a poor prognosis. PHD3 and FIH may be potential therapeutic targets for HCC treatment.