Targeting endogenous DLK1 exerts antitumor effect on hepatocellular carcinoma through initiating cell differentiation.
Targeting endogenous DLK1 exerts antitumor effect on hepatocellular carcinoma through initiating cell differentiation.
复制标题
靶向内源性DLK1通过启动细胞分化对肝细胞癌发挥抗肿瘤作用
DOI：
10.18632/oncotarget.12214
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发表时间：
2016-11-01
期刊：
影响因子：
--
通讯作者：
Han ZG
中科院分区：
文献类型：
--
作者：
Cai CM;Xiao X;Wu BH;Wei BF;Han ZG
癌症干细胞（CSC）负责肿瘤的发生和发展。我们以前的研究表明，Delta-like homolog 1（DLK 1）可能是针对人肝细胞癌（HCC）CSC的治疗靶点。然而，其治疗效果和潜在机制仍不清楚。在这里，我们证明了使用tet诱导的短发夹RNA（shRNA）系统敲低DLK 1显着抑制人肝癌细胞的增殖，球体形成和体内异种移植肿瘤生长。此外，在原位异种移植小鼠模型中，腺病毒介导的DLK 1敲低可以显著减小肿瘤大小，如体内成像方法所示。随后，应用携带小鼠Dlk 1 shRNA的腺病毒载体。结果表明，Dlk 1基因敲低也可以抑制二乙基亚硝胺（DEN）诱导的小鼠肝癌模型中的肿瘤进展。在细胞机制上，DLK 1基因敲低可延迟细胞周期G1-S期的转换，沿着细胞周期蛋白E1和D1的表达降低。DLK 1基因敲减导致肝祖细胞的AFP和EpCAM等分子标志物减少，但分化肝细胞的KRT 18和KRT 19增加。这些数据表明，靶向内源性DLK 1可能通过启动细胞分化而对HCC发挥抗肿瘤作用。
Cancer stem cells (CSCs) are responsible for tumor initiation and progression. We previously showed that Delta-like homolog 1 (DLK1) may be a therapeutic target against the CSCs of human hepatocellular carcinoma (HCC). However, the therapeutic efficacy and underlying mechanism remain unclear. Here we demonstrated that knockdown of DLK1 using a tet-inducible short hairpin RNA (shRNA) system significantly inhibited proliferation, spheroid formation and in vivo xenograft tumor growth of human HCC cells. Furthermore, in an orthotopic xenograft mouse model, adenovirus-mediated DLK1 knockdown could significantly reduce tumor size, as shown by in vivo imaging approach. Subsequently, an adenoviral vector harboring mouse Dlk1 shRNA was applied. The results showed that Dlk1 knockdown also could inhibit tumor progression in a diethylnitrosamine (DEN) induced mouse HCC model. At cellular mechanism, DLK1 knockdown delayed the cell cycle G1-S transition, along with the decreased expression of cyclin E1 and D1. Significantly, DLK1 knockdown resulted in the decrease of molecular markers such as AFP and EpCAM for hepatic progenitor cells, but the increase of KRT18 and KRT19 for the differentiated hepatocytes. The collective data indicated that targeting endogenous DLK1 may exert antitumor effect on HCCs possibly through initiating cell differentiation.