Last Updated: 2003-01-28 11:39:15 -0400 (Reuters Health)
NEW YORK (Reuters Health) - Nitric oxide (NO) induces increased expression of matrix metalloproteinase (MMP) mRNA in human melanoma cells, Japanese researchers report. They believe that MMP gene transcription may be associated with tumor progression under inflammatory conditions.
Dr. Hiroyasu Esumi, of the National Cancer Center Research Institute East in Kashiwa, Chiba, and coinvestigators, used the reverse transcription-polymerase chain reaction to investigate expression of MMPs in two melanoma cell lines after exposure to an NO-generating agent. In both cell lines, MMP-1 and MMP-10 mRNA increased, and in one of them MMP-3 and MMP-13 mRNA also increased.
Endogenously produced NO also increased MMP-1 gene expression, the researchers confirmed, and non-NO-generating agents did not. In one of the cell lines, known as C32TG, accumulation of MMP-1 mRNA led to increased MMP-1 protein production.
Dr. Esumi's group suggests that the MAPK pathway regulates the expression of MMP-1 in C32TG cells, because a selective MEK inhibitor and a p38 MAPK inhibitor inhibited the ability of NO to enhance MMP-1 mRNA expression. In addition, they showed enhanced binding activity of the transcription factor AP-1 to DNA through activation of ERK and p38 MAPK.
Deletion and mutation analysis of the MMP-1 promoter indicated a region that responded to NO. "We have found AP-1 like binding sites in this region," the researchers report. "We do not know if they are functional yet but it is likely that there are most probable candidates for this response."
They also note that MMP-1 induction by NO was inhibited by cycloheximide, "suggesting a requirement for de novo protein synthesis." The researchers suspect that the protein synthesized will prove to be related to the AP-1 complex.
Int J Cancer 2003;103:161-168.