Mechanisms of downregulation of transfected E-cadherin cDNA during formation of invasive tumors in syngeneic mice

Loss of E-cadherin expression has been observed both in experimental tumors and in human cancers and is related to invasiveness and poor differentiati on. The E-cadherin-negative mouse mesenchymal tumor cell line MO4 was trans fected with several plasmids expressing mouse E-cadherin cDNA. These plasmi ds differed from each other by the extent of E-cadherin-specific 3' untrans lated region (UTR) sequences and by the use of different constitutive promo ters. Transfectants were isolated that expressed functional E-cadherin in a homogeneous way. In syngeneic mice, such MO4-Ecad transfectants invariably produced malignant fibrosarcoma-like-tumors, which were completely E-cadhe rin-negative at the protein level. Northern blotting revealed that E-cadher in mRNA expression was downregulated in some but not all MOL4-Ecad tumors. Downregulation was caused by mRNA instability triggered by particular 3' UT R sequences. This in vivo downregulation of E-cadherin in malignant MO4-Eca d tumors turned out to be reversible and is likely to be mediated by host f actors to be further identified.