title: Autophagy enhances hepatocellular carcinoma progression by activation of mitochondrial β-oxidation.
abstract: BACKGROUND
  Several types of cancers, including hepatocellular carcinoma (HCC), show resistance to hypoxia and nutrient starvation. Autophagy is a means of providing macromolecules for energy generation under such stressed-conditions. The aim of this study was to clarify the role of autophagy in HCC development under hypoxic conditions.
  
  
  METHODS
  The expression of microtubule-associated protein 1 light chain 3 (LC3), which is a key gene involved in autophagosome formation, was evaluated in human HCC using immunohistochemistry and western blot. The relationship between LC3 and hypoxia-induced factor 1α (HIF1α) expression was examined using real-time PCR. In addition, human HCC cell line Huh7 was treated with pharmacological autophagy-inhibitor and inactive mutant of Atg4B (Atg4B(C74A)) under hypoxic condition to evaluate the effects of hypoxia-induced autophagy on cell survival, intracellular ATP, and mitochondrial β-oxidation.
  
  
  RESULTS
  LC3 was significantly highly expressed in HCC as compared with noncancerous tissues. LC3 expression, correlated with HIF1α expression, was also significantly correlated with tumor size, and only in the context of large tumors, was an independent predictor of HCC recurrence after surgery. In addition, Huh7 treated with autophagy-inhibitor under hypoxia had lower viability, with low levels of intracellular ATP due to impaired mitochondrial β-oxidation.
  
  
  CONCLUSIONS
  Autophagy in HCC works to promote HIF1α-mediated proliferation through the maintenance of intracellular ATP, depending on the activation of mitochondrial β-oxidation. These findings demonstrated the feasibility of anti-autophagic treatment as a potential curative therapy for HCC, and improved understanding of the factors determining adaptive metabolic responses to hypoxic conditions.
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Toshima
authors.forename: Ken
authors.initials: K
authors.lastname: Shirabe
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Shohei
authors.initials: S
authors.lastname: Yoshiya
authors.forename: Toru
authors.initials: T
authors.lastname: Ikegami
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Yoshizumi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Soejima
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ikeda
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001343:Autophagy; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D018450:Disease Progression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D000255:Adenosine Triphosphate