Paradoxical role of autophagy in the dysplastic and tumor-forming stages of hepatocarcinoma development in rats

K. Sun, X. L. Guo, Q. D. Zhao, Y. Y. Jing, X. R. Kou, X. Q. Xie, Y. Zhou, N. Cai, L. Gao, X. Zhao, S. S. Zhang, J. R. Song, D. Li, W. J. Deng, R. Li, M. C. Wu, L. X. Wei*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

76 Citations (Scopus)

Abstract

Many reports have shown that autophagy has a role as both a promoter and inhibitor in tumor development. However, the mechanism of this paradox is unknown. Tumor development is a multistep process. Therefore, we investigated whether the role of autophagy in hepatocarcinoma formation depended on the stage of tumor development. Based on our results, autophagy inhibition by chloroquine had a tumor-promotive effect in the rat model with N-diethylnitrosamine-induced hepatocarcinogenesis in its dysplastic stage (Ds) and a tumor-suppressive effect in its tumor-forming stage (Ts). In the Ds, autophagy inhibition enhanced cell proliferation, DNA damage and inflammatory cytokines expression in liver. These changes were dependent on the upregulation of reactive oxygen species (ROS) that was resulted from autophagy inhibition, and ultimately accelerated the process of hepatocarcinogenesis. However, in the Ts, autophagy inhibition restrained tumor formation by decreasing tumor cell survival and proliferation. In this stage, autophagy inhibition led to excessive ROS accumulation in the tumor, which promoted cell apoptosis, and prominently suppressed tumor cell metabolism. Taken together, our data suggested that autophagy suppressed hepatocarcinogenesis in the Ds by protecting normal cell stability and promoted hepatocarcinogenesis in the Ts by supporting tumor cells growth. Autophagy always had a role as a protector throughout the process of hepatocarcinoma development.

Original languageEnglish
JournalCell Death and Disease
Volume4
Issue number2
DOIs
Publication statusPublished - Feb 2013
Externally publishedYes

Keywords

  • Autophagy
  • Different stages
  • Hepatocarcinoma development
  • Paradoxical role
  • ROS

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