miR-28-5p-IL-34-macrophage feedback loop modulates hepatocellular carcinoma metastasis

Hepatology. 2016 May;63(5):1560-75. doi: 10.1002/hep.28445. Epub 2016 Mar 7.


MicroRNAs (miRNAs) play a critical role in regulation of tumor metastasis. However, the role of these molecules in hepatocellular carcinoma (HCC) has not been fully elucidated. In this study, we employed miRNA-sequencing and identified 22 miRNAs involved in HCC metastasis. One of these, miR-28-5p, was down-regulated in HCCs. This down-regulation correlated with tumor metastasis, recurrence, and poor survival. Biofunctional investigations revealed that miR-28-5p deficiency promoted tumor growth and metastasis in nude mice without altering the in vitro biological characteristics of HCC cells. Through gene expression profiles and bioinformatics analysis, we identified interleukin-34 (IL-34) as a direct target of miR-28-5p, and the effects of miR-28-5p deficiency on HCC growth and metastasis was dependent on IL-34-mediated tumor-associated macrophage (TAM) infiltration. Moreover, we found that TAMs induced by miR-28-5p-IL-34 signaling inhibit miR-28-5p expression on HCC cells by transforming growth factor beta 1, resulting in an miR-28-5p-IL-34-macrophage-positive feedback loop. In clinical HCC samples, miR-28-5p levels were inversely correlated with IL-34 expression and the number of TAMs. Patients with low miR-28-5p expression, high IL-34 levels, and high numbers of TAMs had a poor prognosis with shorter overall survival and time to recurrence.

Conclusion: A miR-28-5p-IL-34-macrophage feedback loop modulates HCC metastasis and serves as a novel prognostic factor as well as a therapeutic target for HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / secondary*
  • Cell Line, Tumor
  • Cell Proliferation
  • Feedback, Physiological
  • Humans
  • Interleukins / physiology*
  • Liver Neoplasms / pathology*
  • Macrophages / physiology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • MicroRNAs / physiology*
  • Transforming Growth Factor beta1 / physiology
  • Tumor Microenvironment


  • IL34 protein, human
  • Interleukins
  • MIRN28 microRNA, human
  • MicroRNAs
  • Transforming Growth Factor beta1