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Journal of Gastroenterology
Published in: Journal of Gastroenterology 5/2014

01-05-2014 | Original Article—Liver, Pancreas, and Biliary Tract

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

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

Published in: Journal of Gastroenterology | Issue 5/2014

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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 (Atg4BC74A) 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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Metadata
Title
Autophagy enhances hepatocellular carcinoma progression by activation of mitochondrial β-oxidation
Authors
Takeo Toshima
Ken Shirabe
Yoshihiro Matsumoto
Shohei Yoshiya
Toru Ikegami
Tomoharu Yoshizumi
Yuji Soejima
Tetsuo Ikeda
Yoshihiko Maehara
Publication date
01-05-2014
Publisher
Springer Japan
Published in
Journal of Gastroenterology / Issue 5/2014
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI
https://doi.org/10.1007/s00535-013-0835-9

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