Uteroglobin (UG) is a multifunctional, secreted protein that has receptor-m
ediated functions. The human UG (hUG) gene is mapped to chromosome 11q12.2-
13.1, a region frequently rearranged or deleted in many cancers. Although h
igh levels of hUG expression are characteristic of the mucosal epithelia of
many organs, hUG expression is either drastically reduced or totally absen
t in adenocarcinomas and in viral-transformed epithelial cells derived from
the same organs. In agreement with these findings, in an ongoing study to
evaluate the effects of aging on UG-knockout mice, 16/16 animals developed
malignant tumors, whereas the wild-type littermates (n = 25) remained appar
ently healthy even after 1 1/2 years. In the present investigation, we soug
ht to determine the effects of induced-expression of hUG in human cancer ce
lls by transfecting several cell lines derived from adenocarcinomas of vari
ous organs with an hUG-cDNA construct. We demonstrate that induced hUG expr
ession reverses at least two of the most important characteristics of the t
ransformed phenotype (i.e., anchorage-independent growth on soft agar and e
xtracellular matrix invasion) of only those cancer cells that also express
the hUG receptor. Similarly, treatment of the nontransfected, receptor-posi
tive adenocarcinoma cells with purified recombinant hUG yielded identical r
esults. Taken together, these data define receptor-mediated, autocrine and
paracrine pathways through which hUG reverses the transformed phenotype of
cancer cells and consequently, may have tumor suppressor-like effects.