Hepatocellular carcinoma-associated mesenchymal stem cells promote hepatocarcinoma progression: Role of the S100A4-miR155-SOCS1-MMP9 axis
Hepatocellular carcinoma-associated mesenchymal stem cells promote hepatocarcinoma progression: Role of the S100A4-miR155-SOCS1-MMP9 axis
复制标题
肝细胞癌相关间充质干细胞促进肝癌进展：S100A4-mIR155-SOCS1-MMP9 轴的作用
DOI：
10.1002/hep.26257
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发表时间：
2013-06-01
期刊：
影响因子：
13.5
通讯作者：
Pei, Xue-Tao
中科院分区：
文献类型：
--
作者：
Yan, Xin-Long;Jia, Ya-Li;Pei, Xue-Tao
癌症相关间充质干细胞（MSC）在调节肿瘤进展中起着关键作用。然而，肝癌相关间充质干细胞（LC-MSCs）和肝细胞癌（HCC）之间的相互作用尚未报道。在这里，我们确定了MSC在HCC组织中的存在。我们还表明LC-MSC显着增强体内肿瘤生长并促进体外肿瘤球形成。LC-MSC还促进原位肝移植模型中的HCC转移。互补DNA（cDNA）微阵列分析显示，S100 A4在LC-MSCs中的表达显著高于来自邻近无癌组织的肝正常MSCs（LN-MSCs）。重要的是，抑制S100 A4导致HCC细胞的增殖和侵袭能力降低，而外源性S100 A4在HCC细胞中的表达导致肿瘤更重和更多的转移部位。我们的结果表明，从LC-MSCs分泌的S100 A4可以促进肝癌细胞的增殖和侵袭。我们发现，与LC-MSCs共培养和S100 A4异位过表达可显著上调HCC细胞中致癌microRNA（miR）-155的表达。miR-155抑制剂显著减弱了S100 A4的侵袭促进作用。这些结果表明，S100 A4通过调节HCC细胞中miR-155的表达发挥其作用。我们证明，从LC-MSC分泌的S100 A4促进miR-155的表达，其介导细胞因子信号转导抑制因子1的下调，导致随后的STAT 3信号转导激活。这促进了基质金属蛋白酶9的表达，导致肿瘤侵袭性增加。结论：LC-MSCs分泌的S100 A4参与了肝癌的发生、发展过程，可能成为肝癌治疗的新靶点。（肝脏学2013）
Cancer-associated mesenchymal stem cells (MSCs) play a pivotal role in modulating tumor progression. However, the interactions between liver cancer-associated MSCs (LC-MSCs) and hepatocellular carcinoma (HCC) remain unreported. Here, we identified the presence of MSCs in HCC tissues. We also showed that LC-MSCs significantly enhanced tumor growth in vivo and promoted tumor sphere formation in vitro. LC-MSCs also promoted HCC metastasis in an orthotopic liver transplantation model. Complementary DNA (cDNA) microarray analysis showed that S100A4 expression was significantly higher in LC-MSCs compared with liver normal MSCs (LN-MSCs) from adjacent cancer-free tissues. Importantly, the inhibition of S100A4 led to a reduction of proliferation and invasion of HCC cells, while exogenous S100A4 expression in HCC cells resulted in heavier tumors and more metastasis sites. Our results indicate that S100A4 secreted from LC-MSCs can promote HCC cell proliferation and invasion. We then found the expression of oncogenic microRNA (miR)-155 in HCC cells was significantly up-regulated by coculture with LC-MSCs and by S100A4 ectopic overexpression. The invasion-promoting effects of S100A4 were significantly attenuated by a miR-155 inhibitor. These results suggest that S100A4 exerts its effects through the regulation of miR-155 expression in HCC cells. We demonstrate that S100A4 secreted from LC-MSCs promotes the expression of miR-155, which mediates the down-regulation of suppressor of cytokine signaling 1, leading to the subsequent activation of STAT3 signaling. This promotes the expression of matrix metalloproteinases 9, which results in increased tumor invasiveness. Conclusion: S100A4 secreted from LC-MSCs is involved in the modulation of HCC progression, and may be a potential therapeutic target. (HEPATOLOGY 2013)