title: Paradoxical role of autophagy in the dysplastic and tumor-forming stages of hepatocarcinoma development in rats.
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.
authors: Medical Sciences Research Center, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors: K
authors: K
authors: Sun
authors: X-L
authors: XL
authors: Guo
authors: Q-d
authors: QD
authors: Zhao
authors: Y-y
authors: YY
authors: Jing
authors: X-r
authors: XR
authors: Kou
authors: X-q
authors: XQ
authors: Xie
authors: Y
authors: Y
authors: Zhou
authors: N
authors: N
authors: Cai
authors: L
authors: L
authors: Gao
authors: X
authors: X
authors: Zhao
authors: S-s
authors: SS
authors: Zhang
authors: J-r
authors: JR
authors: Song
authors: D
authors: D
authors: Li
authors: W-j
authors: WJ
authors: Deng
authors: R
authors: R
authors: Li
authors: M-c
authors: MC
authors: Wu
authors: L-x
authors: LX
authors: Wei
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000401:mortality / Q000517:prevention & control; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage; D004052:Diethylnitrosamine / Q000633:toxicity; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000401:mortality / Q000517:prevention & control; D008297:Male; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015996:Survival Rate; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D016207:Cytokines; D020011:Protective Agents; D017382:Reactive Oxygen Species; D004052:Diethylnitrosamine; D002738:Chloroquine