Thyroid hormone suppresses hepatocarcinogenesis via DAPK2 and SQSTM1-dependent selective autophagy
| العنوان: | Thyroid hormone suppresses hepatocarcinogenesis via DAPK2 and SQSTM1-dependent selective autophagy |
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| المؤلفون: | Ya-Hui Huang, Sheng Ming Wu, Chau Ting Yeh, Chung-Ying Tsai, Cheng Pu Sun, Shen Liang Chen, Wen-Yu Chuang, Hsiang Cheng Chi, Ming Chieh Tsai, Kwang-Huei Lin |
| المصدر: | Autophagy. 12:2271-2285 |
| بيانات النشر: | Informa UK Limited, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Thyroid Hormones, Carcinoma, Hepatocellular, Transcription, Genetic, Carcinogenesis, DNA damage, Down-Regulation, Biology, medicine.disease_cause, 03 medical and health sciences, Sequestosome 1, Sequestosome-1 Protein, Autophagy, medicine, Animals, Humans, Diethylnitrosamine, Phosphorylation, Protein kinase A, education, Molecular Biology, Inflammation, Gene knockdown, education.field_of_study, Receptors, Thyroid Hormone, Liver Neoplasms, Hep G2 Cells, Cell Biology, Ubiquitinated Proteins, Basic Research Paper, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, Death-Associated Protein Kinases, 030104 developmental biology, Liver, Disease Progression, Cancer research, Triiodothyronine, Ectopic expression, DNA Damage |
| الوصف: | 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. |
| تدمد: | 1554-8635 1554-8627 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1b33510337c2cc5797b943123297327cTest https://doi.org/10.1080/15548627.2016.1230583Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....1b33510337c2cc5797b943123297327c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15548635 15548627 |
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