nm23H1 has properties of a metastasis suppressor gene. Although its mechanism of action is unknown, nm23 has been implicated in
transforming growth factor beta 1 (
TGF beta 1) signal transduction. In an earlier study we decreased nm23
mRNA levels 2- to 8-fold by antisense phosphorothiolated
oligonucleotides in two HT29 colon
carcinoma sublines at different stages in
tumor progression with different responses to
TGF beta 1: the
HD3 subline, which shows
TGF beta 1-induced growth arrest and differentiation; and the more tumorigenic U9 subline, whose growth and invasion are stimulated by
TGF beta 1. Only
TGF beta 1-mediated responses in
HD3 cells were inhibited by nm23 antisense oligos, suggesting that nm23 functions in only one
TGF beta 1 signaling pathway. In the current report we have extended this study to cell motility.
HD3 motility was increased by nm23 phosphorothiolated antisense oligos which decrease nm23
mRNA levels, while
HD3 cell motility was conversely decreased by
TGF beta 1 which increases nm23
mRNA levels.
HD3 motility was not increased by basic FGF,
TGF beta 1 or
TGF alpha, while the 13-fold higher basal motility of U9 cells was stimulated 3-fold by basic FGF, 4-fold by
TGF beta 1 and 5-fold by
TGF alpha, but not by
scatter factor. Differences in motility and response to motility factors could not be ascribed to differences in either basal levels of
proteases or modulation of their levels by
TGF beta 1. Both
HD3 and U9 cells displayed equal levels of
urokinase activity and
mRNA, equal expression of the
metalloproteinase inhibitor
TIMP-1, and no detectable
collagenases by zymography. No differential response to
TGF beta 1 was seen in any of these assays. Thus limited cell motility and lack of response to motility factors in
HD3 colon cancer cells could be correlated with expression of nm23 active in signal transduction.