mi R ‐214 and hypoxia down‐regulate N ecl‐2/ CADM 1 and enhance E rb B 2/ E rb B 3 signaling

N ecl‐2/ CADM 1 is down‐regulated by the promoter hypermethylation and/or the loss of heterozygosity at chromosome 11q23.2 in many types of cancers and serves as a tumor suppressor by interacting in cis with E rb B 3 and suppressing the ligand‐induced E rb B 2/ E rb B 3 signaling for cell movement and death. However, the incidence of these epigenetic and genetic abnormalities of N ecl‐2 is 30–60% in these cancers. We investigated here other mechanisms that down‐regulate N ecl‐2. mi R ‐214, that is frequently up‐regulated in a variety of cancers, targeted the 3′ UTR of the N ecl‐2 mRNA directly, suppressed the translation of N ecl‐2 and enhanced the ligand‐induced E rb B 2/ E rb B 3 signaling in human colon cancer C aco‐2 cells. Hypoxia reduced the Necl‐2 protein level in a manner independent of mi R ‐214 or hypoxia‐inducible factor‐1α in C aco‐2 cells. These results indicate that mi R ‐214 and hypoxia are novel regulators that down‐regulate N ecl‐2 and enhance E rb B 2/ E rb B 3 signaling.