title: Thyroid hormone suppresses hepatocarcinogenesis via DAPK2 and SQSTM1-dependent selective autophagy.
abstract: Recent studies have demonstrated a critical association between disruption of cellular thyroid hormone (TH) signaling and the incidence of hepatocellular carcinoma (HCC), but the underlying mechanisms remain largely elusive. Here, we showed that disruption of TH production results in a marked increase in progression of diethylnitrosamine (DEN)-induced HCC in a murine model, and conversely, TH administration suppresses the carcinogenic process via activation of autophagy. Inhibition of autophagy via treatment with chloroquine (CQ) or knockdown of ATG7 (autophagy-related 7) via adeno-associated virus (AAV) vectors, suppressed the protective effects of TH against DEN-induced hepatic damage and development of HCC. The involvement of autophagy in TH-mediated protection was further supported by data showing transcriptional activation of DAPK2 (death-associated protein kinase 2; a serine/threonine protein kinase), which enhanced the phosphorylation of SQSTM1/p62 (sequestosome 1) to promote selective autophagic clearance of protein aggregates. Ectopic expression of DAPK2 further attenuated DEN-induced hepatoxicity and DNA damage though enhanced autophagy, whereas, knockdown of DAPK2 displayed the opposite effect. The pathological significance of the TH-mediated hepatoprotective effect by DAPK2 was confirmed by the concomitant decrease in the expression of THRs and DAPK2 in matched HCC tumor tissues. Taken together, these findings indicate that TH promotes selective autophagy via induction of DAPK2-SQSTM1 cascade, which in turn protects hepatocytes from DEN-induced hepatotoxicity or carcinogenesis.
authors.affiliation: a Department of Biochemistry , College of Medicine, Chang-Gung University , Taoyuan , Taiwan.
authors.forename: Hsiang-Cheng
authors.initials: HC
authors.lastname: Chi
authors.affiliation: b Department of Life Sciences , National Central University , Jhongli , Taiwan.
authors.forename: Shen-Liang
authors.initials: SL
authors.lastname: Chen
authors.affiliation: a Department of Biochemistry , College of Medicine, Chang-Gung University , Taoyuan , Taiwan.
authors.forename: Chung-Ying
authors.initials: CY
authors.lastname: Tsai
authors.affiliation: c Department of Pathology , Chang Gung Memorial Hospital and Chang Gung University College of Medicine , Taoyuan , Taiwan.
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Chuang
authors.affiliation: d Liver Research Center, Chang Gung Memorial Hospital , Linkou, Taoyuan , Taiwan.
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Huang
authors.affiliation: e Department of Nursing , Chang-Gung University of Science and Technology , Taoyuan , Taiwan.|f Department of General Surgery , Chang Gung Memorial Hospital at Chiayi , Taiwan.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Tsai
authors.affiliation: a Department of Biochemistry , College of Medicine, Chang-Gung University , Taoyuan , Taiwan.|g Division of Pulmonary Medicine, Department of Internal Medicine , Shuang Ho Hospital, Taipei Medical University.
authors.forename: Sheng-Ming
authors.initials: SM
authors.lastname: Wu
authors.affiliation: h Institute of Biomedical Sciences, Academia Sinica , Taipei , Taiwan.
authors.forename: Cheng-Pu
authors.initials: CP
authors.lastname: Sun
authors.affiliation: d Liver Research Center, Chang Gung Memorial Hospital , Linkou, Taoyuan , Taiwan.
authors.forename: Chau-Ting
authors.initials: CT
authors.lastname: Yeh
authors.affiliation: a Department of Biochemistry , College of Medicine, Chang-Gung University , Taoyuan , Taiwan.|d Liver Research Center, Chang Gung Memorial Hospital , Linkou, Taoyuan , Taiwan.
authors.forename: Kwang-Huei
authors.initials: KH
authors.lastname: Lin
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D004249:DNA Damage; D064550:Death-Associated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004052:Diethylnitrosamine; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D000071456:Sequestosome-1 Protein / Q000378:metabolism*; D013963:Thyroid Hormones / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014284:Triiodothyronine / Q000494:pharmacology; D057149:Ubiquitinated Proteins / Q000378:metabolism
chemical_list: D011988:Receptors, Thyroid Hormone; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D013963:Thyroid Hormones; D057149:Ubiquitinated Proteins; D014284:Triiodothyronine; D004052:Diethylnitrosamine; C579104:DAPK2 protein, human; D064550:Death-Associated Protein Kinases; C579103:dapk2 protein, mouse
keywords: DAPK2; HCC; SQSTM1/p62; THR; selective autophagy