title: Identification of a mitochondrial defect gene signature reveals NUPR1 as a key regulator of liver cancer progression.
abstract: Many cancer cells require more glycolytic adenosine triphosphate production due to a mitochondrial respiratory defect. However, the roles of mitochondrial defects in cancer development and progression remain unclear. To address the role of transcriptomic regulation by mitochondrial defects in liver cancer cells, we performed gene expression profiling for three different cell models of mitochondrial defects: cells with chemical respiratory inhibition (rotenone, thenoyltrifluoroacetone, antimycin A, and oligomycin), cells with mitochondrial DNA depletion (Rho0), and liver cancer cells harboring mitochondrial defects (SNU354 and SNU423). By comparing gene expression in the three models, we identified 10 common mitochondrial defect-related genes that may be responsible for retrograde signaling from cancer cell mitochondria to the intracellular transcriptome. The concomitant expression of the 10 common mitochondrial defect genes is significantly associated with poor prognostic outcomes in liver cancers, suggesting their functional and clinical relevance. Among the common mitochondrial defect genes, we found that nuclear protein 1 (NUPR1) is one of the key transcription regulators. Knockdown of NUPR1 suppressed liver cancer cell invasion, which was mediated in a Ca(2+) signaling-dependent manner. In addition, by performing an NUPR1-centric network analysis and promoter binding assay, granulin was identified as a key downstream effector of NUPR1. We also report association of the NUPR1-granulin pathway with mitochondrial defect-derived glycolytic activation in human liver cancer.
  
  
  CONCLUSIONS
  Mitochondrial respiratory defects and subsequent retrograde signaling, particularly the NUPR1-granulin pathway, play pivotal roles in liver cancer progression.
authors.affiliation: Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea.|Department of Biomedical Science, Graduate School, Ajou University, Suwon, Korea.
authors.forename: Young-Kyoung
authors.initials: YK
authors.lastname: Lee
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon, Korea.|Department of Biomedical Science, Graduate School, Ajou University, Suwon, Korea.
authors.forename: Byul A
authors.initials: BA
authors.lastname: Jee
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon, Korea.|Department of Biomedical Science, Graduate School, Ajou University, Suwon, Korea.
authors.forename: So Mee
authors.initials: SM
authors.lastname: Kwon
authors.affiliation: Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Young-Sil
authors.initials: YS
authors.lastname: Yoon
authors.affiliation: Department of Surgery, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Wei Guang
authors.initials: WG
authors.lastname: Xu
authors.affiliation: Department of Surgery, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Wang
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Xin Wei
authors.initials: XW
authors.lastname: Wang
authors.affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Snorri S
authors.initials: SS
authors.lastname: Thorgeirsson
authors.affiliation: Department of Biomedical Sciences and Hypoxia-Related Disease Research Center, Inha University College of Medicine, Incheon, Korea.
authors.forename: Jae-Seon
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon, Korea.|Department of Biomedical Science, Graduate School, Ajou University, Suwon, Korea.
authors.forename: Hyun Goo
authors.initials: HG
authors.lastname: Woo
authors.affiliation: Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea.|Department of Biomedical Science, Graduate School, Ajou University, Suwon, Korea.
authors.forename: Gyesoon
authors.initials: G
authors.lastname: Yoon
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008928:Mitochondria / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009363:Neoplasm Proteins; C491643:NUPR1 protein, human