Journal of Experimental & Clinical Cancer Research (Jun 2017)

MiR21 sensitized B-lymphoma cells to ABT-199 via ICOS/ICOSL-mediated interaction of Treg cells with endothelial cells

  • Zhong Zheng,
  • Peng-Peng Xu,
  • Li Wang,
  • Hui-Jin Zhao,
  • Xiang-Qin Weng,
  • Hui-Juan Zhong,
  • Bin Qu,
  • Jie Xiong,
  • Yan Zhao,
  • Xue-Feng Wang,
  • Anne Janin,
  • Wei-Li Zhao

DOI
https://doi.org/10.1186/s13046-017-0551-z
Journal volume & issue
Vol. 36, no. 1
pp. 1 – 10

Abstract

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Abstract Background MicroRNAs (miRs) are involved in tumor progression by regulating tumor cells and tumor microenvironment. MiR21 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological impact on tumor microenvironment remains unclear. Methods MiR21 was assessed by quantitative RT-PCR in patients with newly diagnosed DLBCL. The mechanism of action of miR21 on lymphoma progression and tumor angiogenesis was examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model. Results Serum miR21 was significantly elevated in patients and associated with advanced disease stage, International Prognostic Index indicating intermediate-high and high-risk, and increased tumor angiogenesis. When co-cultured with immune cells and endothelial cells, miR21-overexpressing B-lymphoma cells were resistant to chemotherapeutic agents, but sensitive to Bcl-2 inhibitor ABT-199, irrespective of Bcl-2 expression on lymphoma cells. In both co-culture systems of Bcl-2positive and Bcl-2negative B-lymphoma cells, miR21 induced inducible co-stimulator (ICOS) expression on regulatory T (Treg) cells. Through crosstalking with Treg cells by ICOS ligand (ICOSL), endothelial cells were activated, resulting in stimulation of Bcl-2 expression and vessel formation. ABT-199 directly targeted Bcl-2 on endothelial cells, induced endothelial cell apoptosis and inhibited tumor angiogenesis. In a murine xenograft model established with subcutaneous injection of B-lymphoma cells, ABT-199 particularly retarded the growth of miR21-overexpressing tumors, consistent with the induction of endothelial cell apoptosis and inhibition of tumor angiogenesis. Conclusions As a serum oncogenic biomarker of B-cell lymphoma, miR21 indicated B-lymphoma cell sensitivity to ABT-199 via ICOS/ICOSL-mediated interaction of Treg cells with endothelial cells.

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