近日來自軍事醫(yī)學科學院的研究人員在新研究中,，揭示了間充質(zhì)干細胞(MSCs)在肝癌進程中發(fā)揮重要作用及其機制,。相關(guān)論文發(fā)表在在國際著名肝臟疾病雜志Hepatology上（最新影響因子11.665）上,。
軍事醫(yī)學科學院輸血研究所的裴雪濤（Xue-Tao Pei）教授和岳文（Wen Yue）研究員為這篇文章的共同通訊作者,。裴雪濤主要從事干細胞生物學與再生醫(yī)學的基礎(chǔ)及應(yīng)用研究。在國內(nèi)外學術(shù)雜志發(fā)表論著100余篇,。2005年曾于第2屆世界再生醫(yī)學大會獲得唯一最高榮譽獎——Paul H Fraisse （保羅?弗雷澤）“最佳科學貢獻獎”,，這一殊榮是中國科學家在該領(lǐng)域獲得的最高獎項。岳文研究員主要從事干細胞發(fā)育分化調(diào)控機制,，尤其是表觀遺傳學調(diào)控機制的研究,。
間充質(zhì)干細胞（MSCs）是干細胞家族的重要成員。這種紡錘形細胞能分化為成骨細胞,、脂肪細胞,、神經(jīng)細胞及多種結(jié)締組織細胞。其高度自我更新能力,，較弱的免疫源性,，易于體外分離培養(yǎng)、擴增,，容易導入外源基因等特性,，使之在細胞治療和基因治療方面顯示出廣闊的應(yīng)用前景，MSCs基礎(chǔ)和臨床應(yīng)用研究已經(jīng)成為生物醫(yī)學研究的熱點和前沿,。
近年來,，MSCs和腫瘤細胞的相互關(guān)系也引起了學者的關(guān)注。然而大量實驗結(jié)果表明MSCs和腫瘤的關(guān)系存在兩面性：一方面研究表明MSCs抑制腫瘤細胞生長,，另有研究卻表明MSCs能夠促進腫瘤的生長和轉(zhuǎn)移,，甚至有研究報道MSCs能發(fā)生惡性轉(zhuǎn)化，獲得腫瘤細胞的相關(guān)生物學特性,。目前,，尚未有肝癌相關(guān)的MSCs (LC-MSCs)與肝癌之間相互作用的相關(guān)報道。
在這篇文章中,，研究人員首次確定了肝癌組織中MSCs的存在,。他們還分別在體內(nèi)外實驗中證實,，LC-MSCs顯著促進了腫瘤生長以及瘤細胞球形成。在原位肝移植模型中,，研究人員證實LC-MSCs促進了肝癌轉(zhuǎn)移,。cDNA微陣列分析表明，相比來自鄰近無癌組織的肝臟正常MSCs (LN-MSCs),，LC-MSCs中的S100A4表達顯著增高,。重要的是，抑制S100A4可導致肝癌細胞增殖和侵襲受到抑制,。而在肝癌細胞中外源性表達S100A4則可導致腫瘤增大,，轉(zhuǎn)移灶增多。研究結(jié)果表明LC-MSCs分泌的S100A4促進了肝癌細胞增殖和侵襲,。
隨后,，研究人員證實，S100A4異位表達及LC-MSCs共培養(yǎng)可顯著上調(diào)肝癌細胞中致癌miR-155表達,。采用miR-155抑制劑即可顯著減弱S100A4的促侵襲效應(yīng),。這些結(jié)果表明S100A4是通過調(diào)控肝癌細胞中的miR-155表達來發(fā)揮作用。研究人員證實LC-MSCs分泌的S100A4促進了miR-155表達,，轉(zhuǎn)而介導了細胞因子信號轉(zhuǎn)導抑制因子1(suppressor of cytokine signaling-1,SOCS1)下調(diào),，導致隨后的STAT3信號激活。由此促進了MMP9表達,，導致腫瘤侵襲性增高,。
新研究表明LC-MSCs通過分泌S100A4參與調(diào)控了肝癌進程，從而為肝癌治療提供了一個潛在的靶點,。(生物谷Bioon.com)
DOI: 10.1002/hep.26257
PMC:
PMID:
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.
