Thyroid hormone suppresses hepatocarcinogenesis via DAPK2 and SQSTM1-dependent selective autophagy

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題名:	Thyroid hormone suppresses hepatocarcinogenesis via DAPK2 and SQSTM1-dependent selective autophagy
作者:	陳盛良;Chi, Hsiang-Cheng;Chen, Shen-Liang;Tsai, Chung-Ying;Chuang, Wen-Yu;Huang, Ya-Hui;Tsai, Ming-Ming;Wu, Sheng-Ming;Sun, Cheng-Pu;Yeh, Chau-Ting;Lin, Kwang-Huei
貢獻者:	生醫理工學院生命科學系
關鍵詞:	Animals;Autophagy - drug effects;Basic Research Paper;Carcinogenesis - drug effects;Carcinogenesis - pathology;Carcinoma, Hepatocellular - genetics;Carcinoma, Hepatocellular - pathology;DAPK2;Death-Associated Protein Kinases - genetics;Death-Associated Protein Kinases - metabolism;Diethylnitrosamine;Disease Progression;DNA Damage;Down-Regulation - drug effects;Gene Expression Regulation, Neoplastic - drug effects;HCC;Hep G2 Cells;Humans;Inflammation - pathology;Liver - drug effects;Liver - metabolism;Liver - pathology;Liver Neoplasms - genetics;Liver Neoplasms - pathology;Male;Mice, Inbred C57BL;Phosphorylation - drug effects;Receptors, Thyroid Hormone - metabolism;selective autophagy;Sequestosome-1 Protein - metabolism;SQSTM1/p62;THR;Thyroid Hormones - pharmacology;Transcription, Genetic - drug effects;Triiodothyronine - pharmacology;Ubiquitinated Proteins - metabolism
日期:	2016-12-01
上傳時間:	2026-04-23 11:14:07 (UTC+8)
出版者:	Landes Bioscience;United States: Taylor & Francis
摘要:	摘要： 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. 其他題名： Autophagy 出版者： United States: Taylor & Francis 出版日期： 2016-12-01 出處： Autophagy, 2016-12, Vol.12 (12), p.2271-2285 資源來源： Taylor & Francis Journals AutoHoldings 版權： 2016 Taylor & Francis 2016 版權： 2016 Taylor & Francis 2016 Taylor & Francis 識別號： ISSN: 1554-8627 識別號： ISSN: 1554-8635 識別號： EISSN: 1554-8635 識別號： DOI: 10.1080/15548627.2016.1230583 識別號： PMID: 27653365
顯示於類別:	[生命科學系] 期刊論文

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