title: Prolyl hydroxylase domain protein 3 and asparaginyl hydroxylase factor inhibiting HIF-1 levels are predictive of tumoral behavior and prognosis in hepatocellular carcinoma.
abstract: 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.
authors.affiliation: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan 430030, China.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Ma
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Shuyao
authors.initials: S
authors.lastname: Hua
authors.affiliation: Department of Surgery, Liyuan Hospital, Huazhong University of Science and Technology, Wuhan 430077, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Sumei
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.|Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541001, China.|Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Guilin 541001, China.
authors.forename: Songqing
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.affiliation: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan 430030, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism*; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011379:Prognosis; D016016:Proportional Hazards Models; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000378:metabolism*; D046888:Tissue Array Analysis
chemical_list: D012097:Repressor Proteins; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
keywords: asparaginyl hydroxylase factor inhibiting HIF-1; hepatocellular carcinoma; hypoxia-inducible factors; prognostic factor; prolyl hydroxylase domain-containing proteins