硫氧还蛋白-1减弱脂连蛋白对小鼠移植性肝癌生长的抑制作用

硫氧还蛋白-1 (thioredoxin 1, Trx1)是机体氧化还原调控的重要蛋白质。脂连蛋白(adiponectin, APN)是一种由脂肪组织分泌的细胞因子。二者在癌症特别是肝癌的发展中具有重要调控作用，但其在调控肝癌的进程中是否存在相关性，且改变这种相关性是否直接影响肝癌的发生发展，目前尚未见报道。本文通过分析癌症和肿瘤基因图谱 (The Cancer Genome Atlas, TCGA) 数据库中大量肝癌患者组织样本数据后，首次发现Trx1与APN在肝癌的进程中存在显著负相关表达。在荷瘤鼠中分别过量表达Trx1、APN和Trx1，采用Western 印迹、免疫组织化学染色及TUNEL等方法检测发现，过量表达的Trx1，缓解了APN引起的瘤内Trx1蛋白水平下降，减弱APN对肿瘤的抑制作用,同时增加Ki67阳性细胞数目，减少细胞凋亡和p-JNK阳性细胞数目。上述结果表明，改变Trx1与APN的负相关性后，APN对肝癌细胞成瘤的抑制作用明显减弱。提示在抑制肝癌细胞生长及肝癌治疗的过程中，调控Trx1及APN的相关性可能起到十分重要的作用，这为临床肝癌的治疗提供更为全面有效的理论机制。

Thioredoxin 1 Alleviates the Inhibitory Effect of APN on Mouse Grafted Hepatocellular Carcinoma

Thioredoxin 1 (Trx1) acts as an important systemic redox regulator. Adiponectin (APN) is secreted by adipose tissues. Although the roles of Trx1 and APN in cancer especially hepatocellular carcinoma (HCC) has been reported, it is necessary to further investigate the relationship between Trx1 and APN in inhibiting HCC development and progression. In order to analyze whether the expression of Trx1 is associated with APN in the pathogenesis of HCC, the Cancer Genome Atlas (TCGA) data set was used in this study and the gene expression profile analyses of liver cancer patients revealed that Trx1 expression was negatively correlated with APN in the progression of HCC. To further investigate the effect of the negative correlation between Trx1 and APN in HCC and its underlying mechanism, HepG2 hepatocellular carcinoma cells overexpressd with APN combined with/without Trx1 were subcutaneously injected into the nude mice. Results of Western blotting, immunohistostaining and TUNEL staining of the xenograft tumors showed that overexpression of Trx1 altered the negative correlation between Trx1 and APN through alleviation of APN induced intratumoral downregulation of Trx1. Moreover, overexpression of Trx1 resulted in an increase of Ki67 positive cells and a decrease of cell apoptosis and phosphorylated JNK positive cells induced by APN. Taken together, these findings suggested that the suppressive effect of APN on tumor growth was significantly depressed by the altered Trx1-APN correlation. The regulatory role of the negative correlation between Trx1 and APN on hepatocarcinogenesis might provide a potential and effective rationale for clinical therapy of HCC.