Autophagy enhances hepatocellular carcinoma progression by activation of mitochondrial β-oxidation

Takeo Toshima, Ken Shirabe, Yoshihiro Matsumoto, Shohei Yoshiya, Toru Ikegami, Tomoharu Yoshizumi, Yuji Soejima, Tetsuo Ikeda, Yoshihiko Maehara

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)907-916
Number of pages10
JournalJournal of gastroenterology
Volume49
Issue number5
DOIs
Publication statusPublished - May 2014

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Autophagy
Hepatocellular Carcinoma
Light
Adenosine Triphosphate
Neoplasms
Microtubule-Associated Proteins
Starvation
Hypoxia
Real-Time Polymerase Chain Reaction
Cell Survival
Western Blotting
Immunohistochemistry
Maintenance
Pharmacology
Recurrence
Cell Line
Food
Therapeutics
Genes

All Science Journal Classification (ASJC) codes

  • Gastroenterology

Cite this

Autophagy enhances hepatocellular carcinoma progression by activation of mitochondrial β-oxidation. / Toshima, Takeo; Shirabe, Ken; Matsumoto, Yoshihiro; Yoshiya, Shohei; Ikegami, Toru; Yoshizumi, Tomoharu; Soejima, Yuji; Ikeda, Tetsuo; Maehara, Yoshihiko.

In: Journal of gastroenterology, Vol. 49, No. 5, 05.2014, p. 907-916.

Research output: Contribution to journalArticle

Toshima, Takeo ; Shirabe, Ken ; Matsumoto, Yoshihiro ; Yoshiya, Shohei ; Ikegami, Toru ; Yoshizumi, Tomoharu ; Soejima, Yuji ; Ikeda, Tetsuo ; Maehara, Yoshihiko. / Autophagy enhances hepatocellular carcinoma progression by activation of mitochondrial β-oxidation. In: Journal of gastroenterology. 2014 ; Vol. 49, No. 5. pp. 907-916.
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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.",
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AU - Shirabe, Ken

AU - Matsumoto, Yoshihiro

AU - Yoshiya, Shohei

AU - Ikegami, Toru

AU - Yoshizumi, Tomoharu

AU - Soejima, Yuji

AU - Ikeda, Tetsuo

AU - Maehara, Yoshihiko

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N2 - 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.

AB - 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.

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