Hepatology：间充质干细胞在肝癌进程中的作用机制

近日来自军事医学科学院的研究人员在新研究中，揭示了间充质干细胞(MSCs)在肝癌进程中发挥重要作用及其机制。相关论文发表在在国际著名肝脏疾病杂志Hepatology上（最新影响因子11.665）上。

军事医学科学院输血研究所的裴雪涛（Xue-Tao Pei）教授和岳文（Wen Yue）研究员为这篇文章的共同通讯作者。裴雪涛主要从事干细胞生物学与再生医学的基础及应用研究。在国内外学术杂志发表论着100余篇。2005年曾于第2届世界再生医学大会获得唯一最高荣誉奖——Paul H Fraisse （保罗?弗雷泽）“最佳科学贡献奖”，这一殊荣是中国科学家在该领域获得的最高奖项。岳文研究员主要从事干细胞发育分化调控机制，尤其是表观遗传学调控机制的研究。

间充质干细胞（MSCs）是干细胞家族的重要成员。这种纺锤形细胞能分化为成骨细胞、脂肪细胞、神经细胞及多种结缔组织细胞。其高度自我更新能力，较弱的免疫源性，易于体外分离培养、扩增，容易导入外源基因等特性，使之在细胞治疗和基因治疗方面显示出广阔的应用前景，MSCs基础和临床应用研究已经成为生物医学研究的热点和前沿。

近年来，MSCs和肿瘤细胞的相互关系也引起了学者的关注。然而大量实验结果表明MSCs和肿瘤的关系存在两面性：一方面研究表明MSCs抑制肿瘤细胞生长，另有研究却表明MSCs能够促进肿瘤的生长和转移，甚至有研究报道MSCs能发生恶性转化，获得肿瘤细胞的相关生物学特性。目前，尚未有肝癌相关的MSCs (LC-MSCs)与肝癌之间相互作用的相关报道。

在这篇文章中，研究人员首次确定了肝癌组织中MSCs的存在。他们还分别在体内外实验中证实，LC-MSCs显着促进了肿瘤生长以及瘤细胞球形成。在原位肝移植模型中，研究人员证实LC-MSCs促进了肝癌转移。cDNA微阵列分析表明，相比来自邻近无癌组织的肝脏正常MSCs (LN-MSCs)，LC-MSCs中的S100A4表达显着增高。重要的是，抑制S100A4可导致肝癌细胞增殖和侵袭受到抑制。而在肝癌细胞中外源性表达S100A4则可导致肿瘤增大，转移灶增多。研究结果表明LC-MSCs分泌的S100A4促进了肝癌细胞增殖和侵袭。

随后，研究人员证实，S100A4异位表达及LC-MSCs共培养可显着上调肝癌细胞中致癌miR-155表达。采用miR-155抑制剂即可显着减弱S100A4的促侵袭效应。这些结果表明S100A4是通过调控肝癌细胞中的miR-155表达来发挥作用。研究人员证实LC-MSCs分泌的S100A4促进了miR-155表达，转而介导了细胞因子信号转导抑制因子1(suppressor of cytokine signaling-1,SOCS1)下调，导致随后的STAT3信号激活。由此促进了MMP9表达，导致肿瘤侵袭性增高。

新研究表明LC-MSCs通过分泌S100A4参与调控了肝癌进程，从而为肝癌治疗提供了一个潜在的靶点。

DOI: 10.1002/hep.26257
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Hepatocellular carcinoma-associated mesenchymal stem cells promote hepatocarcinoma progression: Role of the S100A4-miR155-SOCS1-MMP9 axis

Xin-Long Yan1,†, Ya-Li Jia1,†, Lin Chen1, Quan Zeng1, Jun-Nian Zhou1, Chun-Jiang Fu1,2, Hai-Xu Chen1, Hong-Feng Yuan1, Zhi-Wei Li3, Lei Shi4, Ying-Chen Xu1, Jing-Xue Wang1, Xiao-Mei Zhang5, Li-Juan He1, Chao Zhai1, Wen Yue1,‡,*, Xue-Tao Pei1,*

Recent evidence indicates that 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, for the first time, 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. 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 miR-155 in HCC cells was significantly up-regulated by co-culture 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 downregulation of suppressor of cytokine signaling 1 (SOCS1), leading to the subsequent activation of STAT3 signaling. This promotes the expression of MMP9, which results in increased tumor invasiveness. Conclusion: Our study reveals that S100A4 secreted from LC-MSCs, is involved in the modulation of HCC progression, and may be a potential therapeutic target.