MICA and MICB are stress-induced ligands recognized by the activating receptor NKG2D. A microRNA encoded by human cytomegalovirus downregulates MICB expression by targeting a specific site in the MICB 3′ untranslated region. As this site is conserved among different MICB alleles and a similar site exists in the MICA 3′ untranslated region, we speculated that these sites are targeted by cellular microRNAs. Here we identified microRNAs that bound to these MICA and MICB 3′ untranslated region sequences and obtained data suggesting that these microRNAs maintain expression of MICA and MICB protein under a certain threshold and facilitate acute upregulation of MICA and MICB during cellular stress. These microRNAs were overexpressed in various tumors and we demonstrate here that they aided tumor avoidance of immune recognition.
Bibliographical noteFunding Information:
We thank D. Cosman (Amgen) for the NKG2D-Ig constructs and A. Bernard (Hôpital de L’Archet) for anti-CD99. Supported by the United States–Israel Binational Science Foundation (O.M.), the Israeli Cancer Research Foundation (O.M.), the Israeli Science Foundation (O.M.), the European Consortium (MRTN-CT-2005 and LSCH-CT-2005-518178 to O.M.), the Association for International Cancer Research (O.M.) and the Israel Academy of Sciences and Humanities (Adams Fellowship to N.S.-G.).