Restoring miR122 in human stem-like hepatocarcinoma cells, prompts tumor dormancy through Smad-independent TGF-β pathway.
Restoring miR122 in human stem-like hepatocarcinoma cells, prompts tumor dormancy through Smad-independent TGF-β pathway.
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DOI：
10.18632/oncotarget.11885
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发表时间：
2016-11-01
期刊：
影响因子：
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通讯作者：
Bruix J
中科院分区：
文献类型：
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作者：
Boix L;López-Oliva JM;Rhodes AC;Bruix J
miR 122是成年健康肝脏中普遍存在的miRNA，其负责肝干细胞向肝细胞谱系的分化。它的表达在肝细胞癌（HCC）中经常缺失。我们研究了恢复miR 122表达在一个独特的细胞系中的作用，该细胞系来源于人HCC-BCLC 9细胞，具有固体干细胞样细胞特征，高肿瘤起始能力和不可检测的miR 122表达。我们产生了表达miR 122的稳定的BCLC 9细胞系（BCLC 9-miR 122）。miR 122在BCLC 9细胞中的重新表达降低了细胞增殖速率，并在体内显著减小了肿瘤大小。BCLC 9-miR 122细胞下调MYC、KLF 4、FOXM 1、AKT 2和AKT 3基因的表达，上调FOXO 1和FOXO 3A基因的表达。此外，miR 122转染的细胞降低了AKT 2激酶活化，同时降低了FOXO 1和FOXO 3A蛋白失活。BCLC 9-miR 122中肿瘤大小的减小与p38 MAPK蛋白表达和激活的增加相关，导致磷酸化ERK 1/2与磷酸化p38的比率较低。用TGF-β 1活化抑制剂处理miR 122阳性细胞，通过Smad非依赖性TGF-β反应消除肿瘤休眠程序并恢复细胞增殖率。HCC干细胞样细胞可以通过恢复miR 122表达而定向于细胞分化和肿瘤休眠。我们首次证明，休眠程序是通过Smad非依赖性TGF-β途径实现的。重建miR 122表达是一种有前途的治疗策略，可以同时降低肿瘤侵袭性和减少疾病复发。
miR122 is the prevalent miRNA in adult healthy liver and it is responsible for liver stem cell differentiation towards hepatocyte lineage. Its expression is frequently lost in hepatocellular carcinoma (HCC). We studied the effects of restoring miR122 expression in a distinctive cell line derived from human HCC-BCLC9 cells-with a solid stem-like cell profile, high tumor initiating ability and undetectable miR122 expression. We generated a stable BCLC9 cell line that expresses miR122 (BCLC9-miR122). Restitution of miR122 in BCLC9 cells, decreases cell proliferation rate and reduces significantly tumor size in vivo. BCLC9-miR122 cells down-regulate expression of MYC, KLF4, FOXM1, AKT2 and AKT3 genes and up-regulate FOXO1 and FOXO3A gene expression. In addition, miR122 transfected cells decreased AKT2 kinase activation while decreased FOXO1 and FOXO3A protein inactivation. Reduction in tumor size in BCLC9-miR122 associated with an increase in p38MAPK protein expression and activation leading to a low phospho-ERK1/2 to phospho-p38 ratio. Treatment of miR122 positive cells with an inhibitor of TGFBR1 activation, abolished tumor dormancy program and recovered cell proliferation rate through a Smad-independent TGF-β response. HCC stem-like cells can be directed towards cell differentiation and tumor dormancy by restoring miR122 expression. We demonstrate, for the first time, that dormancy program is achieved through a Smad-independent TGF-β pathway. Reestablishing miR122 expression is a promising therapeutic strategy that would work concurrently reducing tumor aggressiveness and decreasing disease recurrence.