Dicer-regulated microRNAs 222 and 339 promote resistance of cancer cells to cytotoxic T-lymphocytes by down-regulation of ICAM-1

Ryo Ueda, Gary Kohanbash, Kotaro Sasaki, Mitsugu Fujita, Xinmei Zhu, Edward R. Kastenhuber, Heather A. McDonald, Douglas M. Potter, Ronald L. Hamilton, Michael T. Lotze, Saleem A. Khan, Robert W. Sobol, Hideho Okada

Research output: Contribution to journalArticlepeer-review

131 Citations (Scopus)

Abstract

The RNase III endonuclease Dicer plays a key role in generation of microRNAs (miRs). We hypothesized that Dicer regulates cancer cell susceptibility to immune surveillance through miR processing. Indeed, Dicer disruption up-regulated intercellular cell adhesion molecule (ICAM)-1 and enhanced the susceptibility of tumor cells to antigen-specific lysis by cytotoxic T-lymphocytes (CTLs), while expression of other immunoregulatory proteins examined was not affected. Blockade of ICAM-1 inhibited the specific lysis of CTLs against Dicerdisrupted cells, indicating a pivotal role of ICAM-1 in the interaction between tumor cells and CTL. Both miR-222 and -339 are downregulated in Dicer-disrupted cells and directly interacted with the 3′ untranslated region (UTR) of ICAM-1 mRNA. Modulation of Dicer or these miRs inversely correlated with ICAM-1 protein expression and susceptibility of U87 glioma cells to CTL-mediated cytolysis while ICAM-1 mRNA levels remained stable. Immunohistochemical and in situ hybridization analyses of 30 primary glioblastoma tissues demonstrated that expression of Dicer, miR-222, or miR-339 was inversely associated with ICAM-1 expression. Taken together, Dicer is responsible for the generation of the mature miR-222 and -339, which suppress ICAM-1 expression on tumor cells, thereby down-regulating the susceptibility of tumor cells to CTL-mediated cytolysis. This study suggests development of novel miR-targeted therapy to promote cytolysis of tumor cells.

Original languageEnglish
Pages (from-to)10746-10751
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number26
DOIs
Publication statusPublished - 2009 Jun 30
Externally publishedYes

Keywords

  • Dicer
  • Glioma

ASJC Scopus subject areas

  • General

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