MicroRNA-28-5p Regulates Liver Cancer Stem Cell Expansion via IGF-1 Pathway
MicroRNA-28-5p Regulates Liver Cancer Stem Cell Expansion via IGF-1 Pathway
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MicroRNA-28-5p 通过 IGF-1 途径调节肝癌干细胞扩增
DOI：
10.1155/2019/8734362
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发表时间：
2019-12-01
影响因子：
4.3
通讯作者：
Zhou，Xinfeng
中科院分区：
文献类型：
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作者：
Xia，Qing;Han，Tao;Zhou，Xinfeng
背景microRNAs（miRNAs）在肿瘤干细胞（CSCs）的调控中起着重要作用。然而，miRNAs在肝CSC中的作用尚未完全阐明。方法采用Real-time PCR检测肝癌干细胞（CSCs）中miR-miR-28- 5 p的表达。在体内和体外研究了miR-28- 5 p对肝CSC扩增的影响。在患者来源的异种移植物（PDX）中进一步评估HCC中miR-28- 5 p表达与索拉非尼益处之间的相关性。结果在分选的EpCAM和CD 24阳性肝CSC中，miR-28- 5 p表达下调。生物功能研究表明，敲低miR-28- 5 p促进肝CSC自我更新和肿瘤发生。结论miR-28- 5 p过表达可抑制肝CSC的自我更新和肿瘤发生。从机制上讲，我们发现胰岛素样生长因子-1（IGF-1）是肝脏CSC中miR-28- 5 p的直接靶点，miR-28- 5 p对肝脏CSC自我更新和肿瘤发生的影响依赖于IGF-1。miR-28- 5 p和IGF-1之间的相关性在人HCC组织中得到证实。此外，miR-28- 5 p敲低的HCC细胞对索拉非尼治疗更敏感。对患者来源的异种移植物（PDX）的分析进一步证明，miR-28- 5 p可以预测索拉非尼在HCC患者中的益处。结论miR-28- 5 p在肝CSC扩增和索拉非尼应答中起重要作用，miR-28- 5 p是HCC的最佳治疗靶点。
Background MicroRNAs (miRNAs) play a critical role in the regulation of cancer stem cells (CSCs). However, the role of miRNAs in liver CSCs has not been fully elucidated. Methods Real-time PCR was used to detect the expression of miR-miR-28-5p in liver cancer stem cells (CSCs). The impact of miR-28-5p on liver CSC expansion was investigated both in vivo and in vitro. The correlation between miR-28-5p expression and sorafenib benefits in HCC was further evaluated in patient-derived xenografts (PDXs). Results Our data showed that miR-28-5p was downregulated in sorted EpCAM- and CD24-positive liver CSCs. Biofunctional investigations revealed that knockdown miR-28-5p promoted liver CSC self-renewal and tumorigenesis. Consistently, miR-28-5p overexpression inhibited liver CSC's self-renewal and tumorigenesis. Mechanistically, we found that insulin-like growth factor-1 (IGF-1) was a direct target of miR-28-5p in liver CSCs, and the effects of miR-28-5p on liver CSC's self-renewal and tumorigenesis were dependent on IGF-1. The correlation between miR-28-5p and IGF-1 was confirmed in human HCC tissues. Furthermore, the miR-28-5p knockdown HCC cells were more sensitive to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrated that the miR-28-5p may predict sorafenib benefits in HCC patients. Conclusion Our findings revealed the crucial role of the miR-28-5p in liver CSC expansion and sorafenib response, rendering miR-28-5p an optimal therapeutic target for HCC.