Tumorigenicity of cancer stem-like cells derived from hepatocarcinoma is regulated by microRNA-145
Tumorigenicity of cancer stem-like cells derived from hepatocarcinoma is regulated by microRNA-145
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DOI：
10.3892/or.2012.1701
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发表时间：
2012-06-01
期刊：
影响因子：
4.2
通讯作者：
Zhang, Wenjian
中科院分区：
文献类型：
--
作者：
Jia, Yongsheng;Liu, Honglin;Zhang, Wenjian
microRNA通过其影响调节细胞增殖和死亡的基因和蛋白质的表达的能力而与癌症的发生和发展有关。最近的研究发现，干细胞相关基因Sox 2、Oct 4和Klf 4是microRNA-145（miR-145）调控的靶基因，提示miR-145可能在肿瘤干细胞的维持中发挥作用。因此，重要的是要解决miR-145参与癌症干细胞在癌症发生，进展和复发中的关键作用。我们比较了miR-145在来源于肝癌的癌干细胞样细胞（T3 A-A3）、肝癌细胞系BEL-7402和正常肝窦内皮细胞系（LSEC）中的表达。如TaqMan microRNA实时测定所示，与其他细胞系相比，T3 A-A3细胞表达较低的miR-145水平。为了解决miR-145在癌症干细胞中的作用，在T3 A-A3细胞中恢复miR-145。这导致衰老样G，细胞周期停滞，并显著抑制体外克隆细胞扩增和体内异种移植肿瘤生长。此外，miR-145恢复减少体外T3 A-A3细胞的肿瘤球生长和体内裸鼠中T3 A-A3细胞肿瘤形成。此外，miR-145水平的增加抵消了Oct 4水平的降低。miR-145对T3 A-A3细胞中肿瘤抑制的作用在体外和体内都被Oct 4的过表达部分逆转。总的来说，我们的数据表明，miR-145在癌症干细胞致瘤性中起着重要作用，可能通过调节下游靶点Oct 4。
microRNAs are implicated in cancer initiation and progression by their ability to affect the expression of genes and proteins that regulate cell proliferation and death. Recent studies found that the stem cell-related genes Sox2, Oct4 and Klf4 are among the target genes regulated by microRNA-145 (miR-145), suggesting that miR-145 possibly plays a role in the maintenance of cancer stem cells. Therefore, it is important to address the involvement of miR-145 in the key roles of cancer stem cells in cancer initiation, progression and reoccurrence. We compared miR-145 expression in the cancer stem-like cells (T3A-A3) derived from hepatocarcinoma, in the hepatocarcinoma cell line BEL-7402 and in the normal liver sinusoidal endothelial cell line (LSEC). As demonstrated by a TaqMan microRNA real-time assay, T3A-A3 cells express lower miR-145 levels compared to the other cell lines. To address the role of miR-145 in cancer stem cells, miR-145 was restored in T3A-A3 cells. This resulted in senescence-like G, arrest in cell cycling, and significantly inhibited clonogenic cell expansion in vitro and xenograft tumor growth in vivo. Moreover, miR-145 restoration diminished tumorsphere growth of T3A-A3 cells in vitro and T3A-A3 cells tumor formation in nude mice in vivo. Additionally, the increase in miR-145 levels paralleled the decrease in Oct4 levels. The effect of miR-145 on tumor suppression in T3A-A3 cells was partly reversed by overexpression of Oct4 both in vitro and in vivo. Collectively, our data indicate that miR-145 plays an important role in cancer stem cell tumorigenicity, potentially via modulation of the downstream target, Oct4.