title: Hepatocellular carcinoma-associated mesenchymal stem cells promote hepatocarcinoma progression: role of the S100A4-miR155-SOCS1-MMP9 axis.
abstract: 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.
  
  
  CONCLUSIONS
  S100A4 secreted from LC-MSCs is involved in the modulation of HCC progression, and may be a potential therapeutic target. (HEPATOLOGY 2013).
authors: Stem Cells and Regenerative Medicine Lab, Beijing Institute of Transfusion Medicine, Beijing, China.
authors: Xin-Long
authors: XL
authors: Yan
authors: Ya-Li
authors: YL
authors: Jia
authors: Lin
authors: L
authors: Chen
authors: Quan
authors: Q
authors: Zeng
authors: Jun-Nian
authors: JN
authors: Zhou
authors: Chun-Jiang
authors: CJ
authors: Fu
authors: Hai-Xu
authors: HX
authors: Chen
authors: Hong-Feng
authors: HF
authors: Yuan
authors: Zhi-Wei
authors: ZW
authors: Li
authors: Lei
authors: L
authors: Shi
authors: Ying-Chen
authors: YC
authors: Xu
authors: Jing-Xue
authors: JX
authors: Wang
authors: Xiao-Mei
authors: XM
authors: Zhang
authors: Li-Juan
authors: LJ
authors: He
authors: Chao
authors: C
authors: Zhai
authors: Wen
authors: W
authors: Yue
authors: Xue-Tao
authors: XT
authors: Pei
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D018450:Disease Progression; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
chemical_list: C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C108944:SOCS1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C077591:S100A4 protein, human; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9