Abstract：
The effect of triiodothyronine (T3) on the phosphorylation of ERK and the occurrence and development of hepatocellular carcinoma (HCC) is controversial and remains to be clarified. In the present study, both in vitro (hepatoma cell lines) and in vivo (wild-type mice [WT] and mouse models of HCC [HrasG12Vand KrasG12Dtransgenic mice (Hras-Tg and Kras-Tg)]) systems were used to investigate the effect of T3 on p-ERK and hepatocarcinogenesis. The results showed that, in vitro, T3 treatment elevated the levels of p-ERK in hepatoma cells within 30 min. However, p-ERK levels returned to normal after 1 h with no significant effects on cellular proliferation or apoptosis. Interestingly, in vivo, T3 induced early rapid and transient activation of ERK and later persistent downregulation of p-ERK in liver tissues of WT. In Hras-Tg, liver weight, liver/body weight ratio, hepatic tumor numbers and sizes were significantly reduced withT3treatment compared with the untreated group. Furthermore, the levels of albumin, HrasG12V, and p-ERK in hepatic precancerous and tumor tissues were all significantly downregulated with T3 treatment; however, the levels of endogenous Hras were not affected. In WT, T3 also induced downregulation of Albumin in liver tissues, but without influence on the expression of endogenous Hras and p-MEK. Especially, the inhibitory effect of T3 on p-ERK and hepatic tumorigenesis and development without influence on the levels of KrasG12D and p-MEK was further confirmed in Kras-Tg. In conclusion, T3 suppresses hepatic tumorigenesis and development by independently and substantially inhibiting the phosphorylation of ERK in vivo.
摘要：
三碘甲状腺原氨酸(T3)对ERK磷酸化及肝细胞癌(HCC)发生发展的影响存在争议,有待进一步阐明。在本研究中,使用体外（肝癌细胞系）和体内（野生型小鼠[WT]和HCC小鼠模型[HrasG12V和KrasG12D转基因小鼠（Hras-Tg和Kras-Tg）]）系统来研究T3对p-ERK和肝癌发生的影响。结果表明,在体外，T3治疗在30分钟内提高了肝癌细胞中p-ERK的水平。然而,1小时后p-ERK水平恢复正常，对细胞增殖或凋亡没有显着影响。有趣的是,在体内，T3在WT的肝组织中诱导ERK的早期快速和瞬时激活和随后p-ERK的持续下调。在Hras-Tg中，肝脏重量,肝脏/体重比，与未治疗组相比，T3治疗组肝脏肿瘤数量和大小显著减少。此外，白蛋白的水平，HrasG12V,和p-ERK在肝癌前组织和肿瘤组织中的表达均在T3治疗后显著下调;内源性Hras水平不受影响。在WT中,T3还诱导肝组织中白蛋白的下调，但对内源性Hras和p-MEK的表达无影响。尤其是,在Kras-Tg中进一步证实了T3对p-ERK和肝肿瘤发生和发展的抑制作用，而不影响KrasG12D和p-MEK的水平。总之,T3通过在体内独立且基本上抑制ERK的磷酸化来抑制肝肿瘤发生和发展。
