Nm23 mRNA Research Articles

NM23 expression in metastasis of malignant melanoma is a predictive prognostic parameter correlated with survival

The management of patients presenting with metastatic malignant melanoma (MM) is hampered by the substantial variability in survival of these patients and the lack of prognostic markers. In the search for a reliable predictive parameter, we have investigated the expression of the nm23 gene, considered to be a major regulator of the metastatic process. We have analysed by Northern blot the nm23 mRNA level in tumour tissue obtained from metastases of 20 stage II and ten stage III patients with MM. Normal human tissues and benign naevi were simultaneously examined. The level of nm23 expression was highly heterogeneous in MM metastases, with a mean value which was higher than the mean level in normal tissues and naevi. Correlative study was focused on the overall survival following resection of the metastasis in which nm23 Northern blot analysis was performed. Patients displaying higher nm23 expression in metastatic tissue (above the mean level) tended to have a longer survival than others (P = 0.08), and this difference was significant for patients presenting with isolated regional lymph node involvement (P = 0.035). The time from biopsy of the primary MM to the appearance of the first lymph node metastasis also showed a positive correlation with the nm23 mRNA level in this metastasis. The present study is not only in accordance with previous reports showing that the nm23 gene may be implicated in MM progression, but also suggests the reliable value of nm23 expression as a prognostic marker for patients presenting with metastatic MM.

Squamous cell carcinoma of the lung: does the nm23 gene expression correlate to the tumor stage?

We examined the nm23 gene activity in 30 human squamous cell carcinomas of the lung using the Northern blot analysis. Matched healthy lung tissue was available from 10 patients. 26 tumor samples were obtained after resection treatment between 1986 and 1990, 4 additional samples of advanced stages from autopsy. We found a significant increase of nm23 expression towards advanced stages of squamous cell carcinoma (IIIa vs. I: p < 0.015, IV vs. II: p < 0.043, IV vs. I: p < 0.043). Furthermore in stage I and II, poorly differentiated squamous cell carcinomas contained significantly more nm23 mRNA than did moderately differentiated ones (p < 0.027). We could also demonstrate an inverse correlation between the levels of nm23 mRNA and disease-free survival after resection treatment (p < 0.016, chi 2-test for trend). Thus the nm23-gene activity correlates to the tumor stage and the grade of differentiation of the squamous cell carcinoma of the lung, and is therefore of prognostic relevance. It might be possible to describe the biological behaviour of the individual tumor more accurately by the additional measurement of the nm23 mRNA.

Differential nm23 gene expression at the fetal-maternal interface.

The product of the nm23 gene has been proposed as a candidate tumour metastasis suppressor protein. A strong association has been observed between reduced expression of the nm23 gene and acquisition of metastatic behaviour in some tumour cells, including breast cancer and melanoma, but not in others, such as neuroblastoma and colon, cervical and thyroid cancers. During the early gestation period both human and murine trophoblast cells exhibit in vitro invasive properties similar to those of neoplastic cells. Such invasive properties, however, disappear in the late stage of gestation. In the present study, we examined the abundance of nm23 mRNA from various fetal-maternal interface tissues (uterus, decidua, placenta and embryo) during early (day 8), mid (day 14) and late (day 18) stages of gestation in CD1 mice, in order to determine whether nm23 plays any anti-invasive and/or biological roles during gestation. nm23 was found to be expressed in all the tissues during the early and mid stages of gestation. The expression levels were, however, variable among different tissues and development stages. In the early stage, nm23 mRNA levels were the highest and similar among tissues from the uterus, decidua, placenta and embryo. In the mid stage, the mRNA levels were reduced significantly in the uterus, decidua and placenta, but not in the embryo. In the late stage, nm23 mRNA was further reduced to the extent that it could not be seen in the decidua, was barely seen in the uterus and was weakly present in the placenta. However, the mRNA level of the embryo in the late stage was still high and similar to the early stage. We also examined nm23 expression in trophoblast cells from normal human term placenta and a highly metastatic human choriocarcinoma cell line, JAR. nm23 expression was significantly higher in JAR than in normal placenta, indicating that nm23 does not appear to have an anti-metastatic function in this cell line. Several cytokines--interleukin 2 (IL-2), tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma)--and prostaglandin E2 (PGE2) known to modulate tumour growth and metastasis were examined to determine whether they regulate nm23 expression in JAR in vitro. The B16F10 melanoma cell line was used as control. No effect was found in the JAR cell line, whereas TNF-alpha, IFN-gamma and PGE2 down-regulated nm23 expression in the B16F10 cell line.(ABSTRACT TRUNCATED AT 400 WORDS)

Nm23-H1 Expression and disease recurrence after surgical resection of small hepatocellular carcinoma

Background/Aims: The nm23-H1 gene is thought to act as a metastasis-suppressor gene. This study investigates the relationship between nm23-H1 messenger RNA (mRNA) expression and intrahepatic tumor recurrence after surgical resection of small hepatocellular carcinoma. Methods: Seventeen cirrhotic patients with solitary hepatocellular carcinoma <5 cm underwent surgical resection. In 7 patients, the neoplasm recurred after a 12-month median follow-up, whereas the other 10 patients were free of disease after a 30-month median follow-up. Both groups were similar according to age, sex, etiology, status of the underlying liver, tumor size, and other pathological characteristics of the neoplasm. nm23-H1 mRNA levels were assessed in matched tumor and surrounding cirrhotic liver samples by Northern blot hybridization using a 900-base pair probe, which is a BamHI fragment of pnm23-H1 recombinant complementary DNA clone encoding the nm23-H1 human gene. Results: Eight of the 10 patients without disease recurrence during follow-up showed nm23-H1 overexpression with an increase ranging between three- and 45-fold when compared with the nontumoral surrounding liver. Only 1 of the 7 patients with tumor recurrence showed higher nm23-H1 mRNA levels in the tumor than in the nonneoplastic sample (P = 0.013). Conclusions: nm23 mRNA overexpression in small solitary hepatocellular carcinoma is associated with a lower recurrence rate after surgical resection, suggesting that this gene may participate in the metastatic dissemination of this neoplasm.

High levels of nm23-H1 and nm23-H2 messenger RNA in human squamous-cell lung carcinoma are associated with poor differentiation and advanced tumor stages.

Expression of the candidate metastasis-suppressor gene nm23-H1 has been shown to correlate inversely with metastatic potential in some human tumors, but not in all. Until now, few studies have been carried out on the activity of the homologous nm23-H2 gene in human cancer. No nm23 transcription studies exist for human lung cancer so far. To determine whether the nm23 genes could have a metastasis-suppressor function in non-small-cell lung carcinoma (NSCLC), pulmonary sarcoma and carcinoids, we analysed both nm23-HI and nm23-H2 mRNA levels in 37 tumor samples obtained from patients who underwent potentially curative resection between 1986 and 1990, and in 4 metastatic tumors obtained from autopsy. As compared to corresponding healthy lung parenchyma, both nm23-HI and nm23-H2 transcript levels were elevated in 37 of 41 tumors. The increases in nm23 mRNA expression were stronger in advanced stages of squamous-cell carcinoma, large-cell carcinoma, sarcoma and carcinoids than in early stages of the respective tumor types. Within stages I and II of squamous-cell carcinoma, significantly higher nm23 mRNA levels were found in poorly differentiated tumors than in moderately differentiated ones. Moreover, an inverse correlation between nm23 expression and disease-free survival of the patients was observed. In conclusion, our results indicate that the increased nm23 expression in the analysed tumors is not consistent with the proposed metastasis-suppressor function, but the 2 nm23 genes nevertheless may be implicated in the mechanism of tumor progression.

High levels of Nm23 gene expression in advanced stage of thyroid carcinomas

The product of Nm23 gene has been proposed as a candidate tumour metastasis suppressor protein. A strong association has been observed between reduced expression of Nm23 gene and acquisition of metastatic behaviour in some tumour cells including breast cancer and melanoma, but not in others such as colon cancer, neuroblastoma, and cervical cancer. In the present study, we examined the abundance of Nm23 mRNA in 39 thyroid tissue specimens including five multinodular goitres, one follicular adenoma, 26 papillary and three follicular carcinomas, and four anaplastic carcinomas. Nm23 was found to be expressed in all the tissue specimens. The expression was, however, variable in different stages of thyroid carcinoma. In stages I through III of differentiated thyroid carcinoma, the average level of Nm23 gene expression was comparable to that in multinodular goitres. In advanced stage of thyroid carcinoma (stage IV and anaplastic), 2-fold increase of Nm23 expression was noted. No mutations were found in the coding region of the gene. Nm23 mRNA level cannot, therefore, be used as a marker of low metastatic potential in thyroid carcinomas. The association of high level Nm23 expression with anaplastic thyroid carcinoma suggests its correlation with rapid cell proliferation.

Expression of the Antimetastatic Gene nm23 in Human Breast Cancer: An Association WIth Good Prognosis

The nm23 gene was identified in murine melanoma cells, in which its expression is associated with the cells' metastatic potential. Expression of nm23 has been detected in human breast tumors by means of hybridization and immunocytochemistry. We measured nm23 mRNA in 71 patients with primary breast cancer and found variable levels of nm23 expression. The nm23 gene was expressed at higher levels in well-differentiated tumors (P less than .02). There was a significant inverse relationship between nm23 expression and nodal status (P less than .02). Expression of nm23 was positively associated with longer disease-free survival and overall survival, and the relationships were significant (P less than .002 and P less than .003, respectively). This study showed that nm23 expression in human breast cancer was associated with good prognosis and a lack of lymph node metastasis and suggests that the nm23 gene product may play an important role in suppressing the metastatic phenotype.

Dictyostelium Nucleoside Diphospate Kinase Highly Homologous to Nm23 and Awd Proteins Involved in Mammalian Tumor Metastasis and Drosphila Development

Two complementary DNAs (cDNAs) previously isolated, one by functional screening and the other by immunological screening of a Dictyostelium discoideum expression library, encode two proteins, Gip17 and Guk7.2, sharing 71% homology. In the present study, we found that the expression of their messenger RNAs (mRNAs) is developmentally regulated, with a sharp decrease during the first hours of differentiation. The Gip17 protein was purified to homogeneity from D. discoideum amoebas and from recombinant Escherichia coli and was conclusively identified as a nucleoside diphosphate (NDP) kinase. NDP kinases play a major role in synthesis of nucleoside triphosphates and, in many systems, are found associated with guanosine triphosphate (GTP)-binding proteins. We found the Gip17 protein to be 77% homologous to the human Nm23 protein and 75% homologous to the Drosophila melanogaster Awd protein. The levels of murine and human nm23 mRNA and Nm23 protein are significantly reduced in tumor cells of high metastatic potential, suggesting that Nm23 is involved in suppression of mammalian tumor metastasis, and mutants of the awd gene exhibit widespread development abnormalities, suggesting that Awd is involved in D. melanogaster development. The high percentage of homology of the Gip17 and Guk7.2 proteins with the Nm23 and Awd proteins indicates that Nm23 and Awd also have nucleoside diphosphate kinase activity. Possible modulations in the activity of this metabolic enzyme could be related to the altered metabolism of tumor cells and the control of metastatic potential. Our results point to an unexpected role of NDP kinase in development, growth control, and oncogenic transformation.