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Proc Natl Acad Sci U S A. 2009 Jun 30;106(26):10746-51. doi: 10.1073/pnas.0811817106. Epub 2009 Jun 11.

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

Author information

1
Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

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 Dicer-disrupted cells, indicating a pivotal role of ICAM-1 in the interaction between tumor cells and CTL. Both miR-222 and -339 are down-regulated 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.

PMID:
19520829
PMCID:
PMC2705554
DOI:
10.1073/pnas.0811817106
[Indexed for MEDLINE]
Free PMC Article

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