A miR-125b/CSF1-CX3CL1/tumor-associated macrophage recruitment axis controls testicular germ cell tumor growth

Cell Death Dis. 2018 Sep 20;9(10):962. doi: 10.1038/s41419-018-1021-z.


Tumor growth is modulated by crosstalk between cancer cells and the tumor microenvironment. Recent advances have shown that miRNA dysfunction in tumor cells can modulate the tumor microenvironment to indirectly determine their progression. However, this process is poorly understood in testicular germ cell tumors (TGCTs). We reported here that miR-125b was repressed in TGCT samples by epigenetic modifications rather than genetic alternations. Furthermore, miR-125b overexpression significantly alleviated the tumor growth in two NCCIT human embryonic carcinoma xenograft models in vivo, whereas miR-125b did not stimulate autonomous tumor cell growth in vitro. Notably, forced expression of miR-125b in NCCIT embryonic carcinoma cells decreased the abundance of host tumor-associated macrophages (TAMs) within tumor microenvironment. Selective deletion of host macrophages by clodronate abolished the anti-tumoral ability of miR-125b in xenograft models. By RNA profiling, Western blot and luciferase reporter assay, we further observed that miR-125b directly regulated tumor cell-derived chemokine CSF1 and CX3CL1, which are known to control the recruitment of TAMs to tumor sites. Lastly, we found that one set of miRNAs, which are under the regulation of miR-125b, might convergently target CSF1/CX3CL1 in NCCIT cells using miRNA profiling. These findings uncover the anticancer effect of miR-125b via mediating tumor-stroma crosstalk in xenograft models of TGCTs and raise the possibility of targeting miR-125b as miRNA therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Blotting, Western
  • Cell Cycle / genetics
  • Cell Cycle / physiology
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Movement / physiology
  • Cell Proliferation / genetics
  • Cell Proliferation / physiology
  • Chemokine CX3CL1 / genetics
  • Chemokine CX3CL1 / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Epigenesis, Genetic / genetics
  • Gene Expression Regulation, Neoplastic
  • In Situ Nick-End Labeling
  • Macrophage Colony-Stimulating Factor / genetics
  • Macrophage Colony-Stimulating Factor / metabolism*
  • Macrophages / cytology*
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neoplasms, Germ Cell and Embryonal / genetics
  • Neoplasms, Germ Cell and Embryonal / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Testicular Neoplasms / genetics
  • Testicular Neoplasms / metabolism*
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / physiology


  • CSF1 protein, mouse
  • Chemokine CX3CL1
  • MIRN125 microRNA, human
  • MicroRNAs
  • RNA, Small Interfering
  • Macrophage Colony-Stimulating Factor

Supplementary concepts

  • Testicular Germ Cell Tumor