The role of nm23 in transforming growth factor beta 1-mediated adherence and growth arrest.
nm23 has properties of a metastasis suppressor gene and also has been implicated in the control of response to transforming growth factor beta 1 (TGF beta 1) by studies in melanoma cells. In this report, we have examined the role of nm23 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 invasive and tumorigenic U9 subline, which induces tumors 7-fold as large as those induced by HD3 cells with one-half the latency. Analysis by semiquantitative reverse transcription-polymerase chain reaction showed that antisense phosphorothiolated oligonucleotides to the nm23 initiation site (nm23 AS oligos) decreased nm23 mRNA levels 2-8-fold in HD3 and U9 cells when normalized to beta-actin mRNA levels. However, a role for nm23 in TGF beta 1-mediated responses could only be found in HD3 cells. nm23 AS oligos inhibited the differentiation property of cell adherence over 90% in HD3 cells, and this loss of adherence could be partially blocked by concurrent treatment with TGF beta 1. In contrast, U9 cell adherence was not detectably altered by nm23 AS oligos, whether added in the presence or absence of TGF beta 1. The TGF beta 1-induced inhibition of HD3 cell proliferation was blocked by nm23 AS oligos, whereas the TGF beta 1-induced proliferation of U9 cells was unaffected by nm23 AS oligos.(ABSTRACT TRUNCATED AT 250 WORDS)
Hsu
S
S
Laboratory of Gastrointestinal Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Huang
F
F
Wang
L
L
Banerjee
S
S
Winawer
S
S
Friedman
E
E
D001483:Base Sequence; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D015398:Signal Transduction / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D016212:Transforming Growth Factor beta