Thyroid hormone suppresses hepatocarcinogenesis via DAPK2 and SQSTM1-dependent selective autophagy
Thyroid hormone suppresses hepatocarcinogenesis via DAPK2 and SQSTM1-dependent selective autophagy
复制标题
DOI：
10.1080/15548627.2016.1230583
复制
发表时间：
2016-01-01
期刊：
影响因子：
13.3
通讯作者：
Lin, Kwang-Huei
中科院分区：
文献类型：
--
作者：
Chi, Hsiang-Cheng;Chen, Shen-Liang;Lin, Kwang-Huei
最近的研究表明，细胞甲状腺激素（TH）信号的破坏与肝细胞癌（HCC）的发病率之间存在着重要的联系，但其潜在的机制仍然难以捉摸。在这里，我们发现在小鼠模型中，破坏TH的产生导致二乙基亚硝胺（DEN）诱导的HCC的进展显著增加，相反，TH通过激活自噬来抑制致癌过程。通过氯喹（CQ）治疗或通过腺相关病毒（AAV）载体敲低ATG7（自噬相关7）抑制自噬，抑制TH对den诱导的肝损伤和HCC发展的保护作用。数据显示，DAPK2（死亡相关蛋白激酶2，一种丝氨酸/苏氨酸蛋白激酶）的转录激活进一步支持了自噬参与th介导的保护，这增强了SQSTM1/p62 （sequestosome 1）的磷酸化，以促进选择性自噬清除蛋白质聚集体。异位表达DAPK2通过增强自噬进一步减轻den诱导的肝毒性和DNA损伤，而敲低DAPK2则表现出相反的效果。在匹配的HCC肿瘤组织中，thr和DAPK2的表达同时降低，证实了th介导的DAPK2肝保护作用的病理意义。综上所述，这些发现表明TH通过诱导DAPK2-SQSTM1级联促进选择性自噬，从而保护肝细胞免受den诱导的肝毒性或癌变。
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.