BCL11B regulates MICA/B-mediated immune response by acting as a competitive endogenous RNA

Oncogene. 2020 Feb;39(7):1514-1526. doi: 10.1038/s41388-019-1083-0. Epub 2019 Oct 31.

Abstract

Cancer immune surveillance is an important host protection process that inhibits carcinogenesis and maintains cellular homeostasis. The major histocompatibility complex class I-related molecules A and B (MICA and MICB) are NKG2D ligands that play important roles in tumor immune surveillance. In the present study, by a combined bioinformatics prediction and experimental approach, we identify BCL11B 3'-UTR as a putative MICA and MICB ceRNA. We demonstrate in several human cell lines of different origins that the knockdown of BCL11B downregulates surface expression of MICA and MICB. Furthermore, we demonstrate miRNA dependency of BCL11B-mediated MICA and MICB regulation in Dicer knockdown HCT116 cells. In addition, MICA/B-targeting miRNAs (miR-17, miR-93, miR-20a, miR-20b, miR-106a, and miR-106b) repressed the expression of BCL11B by targeting its 3'-UTR. Moreover, we showed that the BCL11B knockdown-mediated downregulation of MICA/B resulted in reduced NK cell elimination in vitro and in vivo through reduced recognition of NKG2D. Of particular significance, BCL11B displays tumor-suppressive properties. The expression of BCL11B is downregulated in colon cancer tissues and associated with a reduced median survival of colon cancer patients. Taken together, our study revealed a new mechanism of BCL11B that prevents immune evasion of cancerous cells by upregulation of the NKG2D ligands MICA and MICB in a ceRNA manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Knockdown Techniques
  • HCT116 Cells
  • HT29 Cells
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Immunity / genetics*
  • Minor Histocompatibility Antigens / metabolism*
  • RNA / genetics*
  • Repressor Proteins / deficiency
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • BCL11B protein, human
  • Histocompatibility Antigens Class I
  • MR1 protein, human
  • Minor Histocompatibility Antigens
  • Repressor Proteins
  • Tumor Suppressor Proteins
  • RNA