title: NDUFA4L2 Fine-tunes Oxidative Stress in Hepatocellular Carcinoma.
abstract: Hepatocellular carcinoma (HCC) lacks effective curative therapy. Hypoxia is commonly found in HCC. Hypoxia elicits a series of protumorigenic responses through hypoxia-inducible factor-1 (HIF1). Better understanding of the metabolic adaptations of HCC cells during hypoxia is essential to the design of new therapeutic regimen.
  
  
  
  Expressions of genes involved in the electron transport chain (ETC) in HCC cell lines (20% and 1% O2) and human HCC samples were analyzed by transcriptome sequencing. Expression of NDUFA4L2, a less active subunit in complex I of the ETC, in 100 pairs of HCC and nontumorous liver tissues were analyzed by qRT-PCR. Student t test and Kaplan-Meier analyses were used for clinicopathologic correlation and survival studies. Orthotopic HCC implantation model was used to evaluate the efficiency of HIF inhibitor.
  
  
  
  NDUFA4L2 was drastically overexpressed in human HCC and induced by hypoxia. NDUFA4L2 overexpression was closely associated with tumor microsatellite formation, absence of tumor encapsulation, and poor overall survival in HCC patients. We confirmed that NDUFA4L2 was HIF1-regulated in HCC cells. Inactivation of HIF1/NDUFA4L2 increased mitochondrial activity and oxygen consumption, resulting in ROS accumulation and apoptosis. Knockdown of NDUFA4L2 markedly suppressed HCC growth and metastasis in vivo HIF inhibitor, digoxin, significantly suppressed growth of tumors that expressed high level of NDUFA4L2.
  
  
  
  Our study has provided the first clinical relevance of NDUFA4L2 in human cancer and suggested that HCC patients with NDUFA4L2 overexpression may be suitable candidates for HIF inhibitor treatment. Clin Cancer Res; 22(12); 3105-17. ©2016 AACR.
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: Robin Kit-Ho
authors.initials: RK
authors.lastname: Lai
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: Iris Ming-Jing
authors.initials: IM
authors.lastname: Xu
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: David Kung-Chun
authors.initials: DK
authors.lastname: Chiu
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: Aki Pui-Wah
authors.initials: AP
authors.lastname: Tse
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: Larry Lai
authors.initials: LL
authors.lastname: Wei
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: Cheuk-Ting
authors.initials: CT
authors.lastname: Law
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: Derek
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong. State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Wong
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: Maria Pik
authors.initials: MP
authors.lastname: Wong
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong. State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong. carmencl@pathology.hku.hk iolng@hku.hk.
authors.forename: Irene Oi-Lin
authors.initials: IO
authors.lastname: Ng
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong. State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong. carmencl@pathology.hku.hk iolng@hku.hk.
authors.forename: Carmen Chak-Lui
authors.initials: CC
authors.lastname: Wong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D015687:Cell Hypoxia / Q000235:genetics*; D045744:Cell Line, Tumor; D004077:Digoxin / Q000494:pharmacology; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics*; D010101:Oxygen Consumption / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D004077:Digoxin; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I