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 sharp contrast, the low frequency of loss at NME1 and its equal distribution in nodal metastasis-positive and -negative patients suggests that inactivation of this gene by allelic loss probably does not play a role in the development of regional metastases from these tumors.
Additional studies demonstrated that the metastasis suppressor activity encoded by the chromosome 17 pter-q23 region is p53-independent and not due to enhanced expression of NM23 protein.
In Northern blot analysis an inverse relationship between metastatic ability and metastasis-suppressor gene, nm23-H1, expression is observed - with clone neo6/C8161.1 expressing the highest level of nm23 transcripts, neo6/C8161.2 and neo6/C8161.3 expressing intermediate levels, and barely detectable levels are seen in C8161.
For example, both the RB gene of retinoblastoma and the p53 gene, which is commonly mutated in breast and colon cancer among others, produce proteins involved in distinct steps of cell cycle control, while the nm23 product prevents metastasis.
A detailed study of the structure and function of the promoter element of the nm23-H1 gene will help in understanding the regulatory mechanisms of nm23 expression and its role in tumor progression, especially in metastasis.
These results suggest that expression of the nm23 genes, especially nm23-H1, is activated, accompanied by c-erbB-2 and c-erbB-3 overexpressions, in early stages of the carcinogenic process of ovarian carcinoma and reduction of nm23-H1 expression occurs in association with lymph nodal and/or distant metastasis.
Our purpose was to use this assay to investigate the role of the putative metastasis suppressor gene nm23-H1 in mammary development and differentiation.
It was suggested that the down-regulation of nm23 gene might have a role in metastasis and invasion in gastric cancer, possibly leading to a poor prognosis.
In addition, there is evidence suggesting a contribution for the p53 and NF1 tumor-suppressor genes, and the nm23metastasis-suppressor gene, in melanoma development or progression.
One gene postulated to play a role in tumour metastasis suppression is NME1 (nm23-H1), and an inverse relationship between NME1 expression and metastatic potential has been observed for some solid tumours.
This overexpression was lost, however, in some advanced cases: 89% and 81% of TNM (tumour, node, metastases) stages 0-II showed Nm23-H1 and -H2 overexpression, respectively, which significantly differed from 47% and 38% of stage III-IV tumours.
Furthermore, carcinomas that had detectable metastasis at the time of surgery were negative fornm23-H1 protein more frequently than those that did not.
These findings indicated that two murine isotypes of nm23 but not those of humans are intimately related with the suppression of metastasis in the murine body.
Furthermore, nm23-H1 mRNA abundance may be a predictor of intrahepatic metastasis, the most important factor correlated with the metastatic potential of hepatocellular carcinoma.