Mesenchymal Stem Cells Promote Hepatocarcinogenesis via lncRNA-MUF Interaction with ANXA2 and miR-34a

Cancer Res. 2017 Dec 1;77(23):6704-6716. doi: 10.1158/0008-5472.CAN-17-1915. Epub 2017 Sep 25.


Accumulating evidence suggests that cancer-associated mesenchymal stem cells (MSC) contribute to the development and metastasis of hepatocellular carcinoma (HCC). Aberrant expression of long noncoding RNAs (lncRNA) has been associated with these processes but cellular mechanisms are obscure. In this study, we report that HCC-associated mesenchymal stem cells (HCC-MSC) promote epithelial-mesenchymal transition (EMT) and liver tumorigenesis. We identified a novel lncRNA that we termed lncRNA-MUF (MSC-upregulated factor) that is highly expressed in HCC tissues and correlated with poor prognosis. Depleting lncRNA-MUF in HCC cells repressed EMT and inhibited their tumorigenic potential. Conversely, lncRNA-MUF overexpression accelerated EMT and malignant capacity. Mechanistic investigations showed that lncRNA-MUF bound Annexin A2 (ANXA2) and activated Wnt/β-catenin signaling and EMT. Furthermore, lncRNA-MUF acted as a competing endogenous RNA for miR-34a, leading to Snail1 upregulation and EMT activation. Collectively, our findings establish a lncRNA-mediated process in MSC that facilitates hepatocarcinogenesis, with potential implications for therapeutic targeting. Cancer Res; 77(23); 6704-16. ©2017 AACR.

MeSH terms

  • Annexin A2 / metabolism
  • Carcinogenesis / genetics*
  • Carcinogenesis / pathology
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / pathology
  • Epithelial-Mesenchymal Transition / genetics*
  • Gene Expression Regulation, Neoplastic / genetics
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Mesenchymal Stem Cells / pathology*
  • MicroRNAs / genetics
  • RNA, Long Noncoding / genetics*
  • Snail Family Transcription Factors / biosynthesis
  • Spheroids, Cellular / pathology
  • Tumor Cells, Cultured
  • Wnt Signaling Pathway


  • ANXA2 protein, human
  • Annexin A2
  • MIRN34 microRNA, human
  • MicroRNAs
  • RNA, Long Noncoding
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • long noncoding RNA MUF, human