MiR-10b downregulates the stress-induced cell surface molecule MICB, a critical ligand for cancer cell recognition by natural killer cells.
Natural killer cells (NK) are a component of innate immunity well known for their potent ability to kill virus-infected or neoplastically transformed cells following stimulation of the NK cell receptor NKG2D. One of the various ligands of NKG2D is MICB, a stress-induced ligand that has been found to be upregulated on the surface of tumor cells. However, there is little knowledge about how this upregulation may occur or how it may be selected against in tumors as a mechanism of immune escape. Here, we report that the metastasis-associated microRNA (metastamir) miR-10b directly binds to the 3' untranslated region of MICB and downregulates its expression. Notably, antagonizing miR-10b action enhanced NKG2D-mediated killing of tumor cells in vitro and enhanced clearance of tumors in vivo. Conversely, overexpression of miR-10b downregulated MICB and impaired elimination of tumor cells. Together, our results define MICB as a novel immune target of miR-10b, implying a direct link between metastasis capability and immune escape from NK cells.
Lautenberg Center for General and Tumor Immunology, The Hebrew University, The BioMedical Research Institute, Hadassah Medical School, Jerusalem, Israel.
Pinchas
P
Tsukerman
Noam
N
Stern-Ginossar
Chamutal
C
Gur
Ariella
A
Glasner
Daphna
D
Nachmani
Yoav
Y
Bauman
Rachel
R
Yamin
Alon
A
Vitenshtein
Noah
N
Stanietsky
Tomer
T
Bar-Mag
Dikla
D
Lankry
Ofer
O
Mandelboim
D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000276:immunology / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000276:immunology; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology
D015395:Histocompatibility Antigens Class I; D008024:Ligands; C098080:MICB antigen; C547183:MIRN10 microRNA, human; D035683:MicroRNAs