| Abstract: |
nm23H1 has properties of a metastasis suppressor gene. Although its mechanism of action is unknown, nm23 has been implicated in transforming growth factor β1 (TGFβ1) 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 TGFβ1: the HD3 subline, which shows TGFβ1induced growth arrest and differentiation; and the more tumorigenic U9 subline, whose growth and invasion are stimulated by TGFβ1. Only TGFβ1-mediated responses in HD3 cells were inhibited by nm23 antisense oligos, suggesting that nm23 functions in only one TGFβ1 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 TGFβ1 which increases nm23 mRNA levels. HD3 motility was not increased by basic FGF, TGFβ1 or TGFα, while the 13-fold higher basal motility of U9 cells was stimulated 3-fold by basic FGF, 4-fold by TGFβ1 and 5-fold by TGFα, 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 TGFβ1. 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 TGFβ1 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. © 1995 Oxford University Press. |
| Keywords: |
signal transduction; controlled study; comparative study; metastasis; colonic neoplasms; cancer cell culture; enzyme activity; transcription factors; tumor suppressor gene; gene expression regulation, neoplastic; molecular sequence data; messenger rna; gene repression; transforming growth factor beta1; cell movement; base sequence; colon carcinoma; ht29 cells; cell motility; genes, tumor suppressor; fibroblast growth factor; transforming growth factor alpha; urokinase; tissue inhibitor of metalloproteinase; oligonucleotides, antisense; growth substances; antisense oligonucleotide; human; priority journal; article; oligodeoxynucleotide phosphorothioate; support, u.s. gov't, p.h.s.
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