title: Autophagy-deficiency in hepatic progenitor cells leads to the defects of stemness and enhances susceptibility to neoplastic transformation.
abstract: Autophagy is a highly conserved and lysosome-dependent degradation process which assists in cell survival and tissue homeostasis. Although previous reports have shown that deletion of the essential autophagy gene disturbs stem cell maintenance in some cell types such as hematopoietic and neural cells, it remains unclear how autophagy-deficiency influences hepatic progenitor cells (HPCs). Here we report that Atg5-deficiency in HPCs delays HPC-mediated rat liver regeneration in vivo. In vitro researches further demonstrate that loss of autophagy decreases the abilities of colony and spheroid formations, and disrupts the induction of hepatic differentiation in HPCs. Meanwhile, autophagy-deficiency increases the accumulations of damaged mitochondria and mitochondrial reactive oxygen species (mtROS) and suppresses homologous recombination (HR) pathway of DNA damage repair in HPCs. Moreover, in both diethylnitrosamine (DEN) and CCl4 models, autophagy-deficiency accelerates neoplastic transformation of HPCs. In conclusion, these findings demonstrate that autophagy contributes to stemness maintenance and reduces susceptibility to neoplastic transformation in HPCs.
authors.affiliation: The Second Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xue
authors.affiliation: The Second Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Hu
authors.affiliation: The Second Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Ruiliang
authors.initials: R
authors.lastname: Ge
authors.affiliation: The Second Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Lixue
authors.initials: L
authors.lastname: Yang
authors.affiliation: The Second Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.affiliation: The Second Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Li
authors.affiliation: The Second Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China. Electronic address: Sunyanfu_smmu@163.com.
authors.forename: Yanfu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: The Second Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China. Electronic address: Wangkui_smmu@163.com.
authors.forename: Kui
authors.initials: K
authors.lastname: Wang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D002251:Carbon Tetrachloride; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D004052:Diethylnitrosamine; D004195:Disease Models, Animal; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D008115:Liver Regeneration / Q000187:drug effects / Q000235:genetics; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D014162:Transfection; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism
chemical_list: C545865:Atg5 protein, rat; C561242:Atg7 protein, rat; D000071187:Autophagy-Related Protein 5; D011506:Proteins; D017382:Reactive Oxygen Species; D004052:Diethylnitrosamine; D002251:Carbon Tetrachloride; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes
keywords: Autophagy; DNA damage repair; Hepatic progenitor cells; Neoplastic transformation; Stemness