Let-7g targets collagen type I alpha2 and inhibits cell migration in hepatocellular carcinoma.
Let-7g targets collagen type I alpha2 and inhibits cell migration in hepatocellular carcinoma.
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DOI：
10.1016/j.jhep.2009.12.025
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发表时间：
2010-05
影响因子：
25.7
通讯作者：
Wang XW
中科院分区：
文献类型：
--
作者：
Ji J;Zhao L;Budhu A;Forgues M;Jia HL;Qin LX;Ye QH;Yu J;Shi X;Tang ZY;Wang XW
肝细胞癌（HCC）是一种侵袭性癌症，预后差，主要是由于转移。microRNA是一种内源性小分子非编码RNA，调节细胞基因表达，并与肿瘤发生有功能联系。利用微阵列分析，我们最近发现了20个与HCC转移相关的miRNAs。在这里，我们对其中一种microRNA let-7 g进行了进一步的分析，以确定它是否与HCC转移有功能联系。实时定量聚合酶链反应用于确定肝癌临床标本中let-7 g成熟转录物的水平及其与患者生存的相关性。在HCC细胞系中进行let-7 g的异位表达以评估其对细胞生长、迁移和侵袭的影响。我们证实了let-7 g的水平在转移性HCC中显著低于无转移的HCC。此外，let-7 g在肿瘤中的低表达预示着HCC患者的生存率低。功能研究表明let-7 g的异位表达显著抑制HCC细胞的迁移和细胞生长。计算机模拟分析显示，可溶性胶原蛋白成员是let-7 g的潜在靶点。结论：Ⅰ型胶原α2（COL 1A 2）与let-7 g在HCC中的表达呈负相关。实验证实COL 1A 2是let-7 g的直接靶标。此外，COL 1A 2的加入抵消了let-7 g对细胞迁移的抑制作用。这些结果表明let-7 g可能部分通过靶向COL 1A 2抑制HCC转移。
Hepatocellular carcinoma (HCC) is an aggressive cancer with a poor prognosis mainly due to metastasis. MicroRNAs are endogenous small noncoding RNAs that regulate cellular gene expression and are functionally linked to tumourigenesis. Using microarray analysis, we recently identified 20 miRNAs associated with HCC metastasis. Here, we carried out further analyses on one of these microRNAs, let-7g, to determine whether it is functionally linked to HCC metastasis. Quantitative real-time polymerase chain reaction was used to determine the level of mature let-7g transcript in HCC clinical specimens and its correlation with patient survival. Ectopic expression of let-7g was carried out in HCC cell lines to assess its influence on cell growth, migration and invasion. We confirmed that the level of let-7g was significantly lower in metastatic HCCs compared to metastasis-free HCCs. Moreover, low let-7g expression in a tumour was predictive of poor survival in HCC patients. Functional studies indicated that ectopic expression of let-7g significantly inhibits HCC cell migration and cell growth. In-silico analysis revealed members of soluble collagens as potential targets of let-7g. Consistently, the levels of type I collagen α2 (COL1A2) and let-7g were inversely correlated in HCC clinical specimens. COL1A2 was experimentally validated as a direct target of let-7g. Moreover, addition of COL1A2 counteracted the inhibitory effect of let-7g on cell migration. These results suggest that let-7g may suppress HCC metastasis partially through targeting COL1A2.