Cancer metastasis, a complex and sequential network of cellular events involved in the migration and establishment of malignant cells from original site to distant foci, is an important and significant contributor to morbidity and mortality of cancer patients. Despite the clinical importance of cancer metastasis, its molecular and biochemical mechanism remains unclear. The identification of tumor suppressor gene confirmed that metastasis might involve the functional loss of genes that maintain the cellular differentiation optimally. Metastasis suppressor is defined by the ability to reduce the metastatic property of cancer cells without affecting its tumorigenesis. Since NM23 was first identified in 1988 as a metastasis suppressor, several metastasis suppressor genes have been identified and characterized. In this article, we review the complex and multi-step process of cancer metastasis and describe the recent progress of metastasis suppressors in the studies of identified. Consequently, we hope to introduce the new therapeutic target for the metastasis suppressors in cancer patients.
English Abstract ; *Genes, Tumor Suppressor ; Humans ; Neoplasm Metastasis/genetics/*physiopathology ; Nucleoside-Diphosphate Kinase/genetics/metabolism

OBJECTIVETo study the expression of p16 and nm23 genes in salivary gland tumors and the relation of P16 and nm23 proteins with fumorigenesis of salivary gland tumors.

METHODSExpression of P16 and nm23 proteins was examined by SABC immunohistochemical method in 39 cases of paraffin blocks of normal salivary gland tissues and salivary gland tumors.

RESULTSP16 and nm23 protein positive staining were mainly found in the cytoplasm and cytoblast of all salivary gland tissues. Positive rate of P16 protein expression was 76.9% (10/13) and 40.9% (9/22) in benign and malignant salivary gland tumors, respectively. There was significant difference between P16 protein expression of benign and malignant tumors by chi 2 test (P < 0.05). mm23 protein positive staining was found in 84.6% (11/13) and 45.5% (10/22) of benign and malignant tumors respectively. The expression of nm23 protein in benign and malignant tumors was significantly different (P < 0.05). There was no correlation of the expression of P16 and nm23 in salivary gland tumors was found (P > 0.05).

CONCLUSIONp16 and nm23 genes may play an important role in different sides in salivary gland tumorigenesis and the reduce of the expression of p16 and nm23 genes may contribute to the generation of malignant salivary gland tumors.

Adenoma, Pleomorphic ; genetics ; metabolism ; Carcinoma, Mucoepidermoid ; genetics ; metabolism ; Cyclin-Dependent Kinase Inhibitor p16 ; biosynthesis ; genetics ; Humans ; Immunohistochemistry ; NM23 Nucleoside Diphosphate Kinases ; Nucleoside-Diphosphate Kinase ; Protein Biosynthesis ; Proteins ; genetics ; Salivary Gland Neoplasms ; genetics ; metabolism ; Salivary Glands ; metabolism

OBJECTIVETo transfect nm23-H1 into the BcaCD885 cell lines in order to get safe high-efficiency and low-toxicity, and to find out whether nm23-H1 could affect the invasion and metastases ability of BcaCD885 cell lines.

METHODSLipofect was used to transfect nm23-H1 into BcaCD885 cell lines; immunohistochemistry was used to detect the difference expression of nm23-H1 between transfected and non-transfected cell lines; then transwell-room and wash way were used to detect the difference of invasion and metastases ability between transfected and non-transfected cell lines.

RESULTSPCMV-NEO-BAM system gave the stability expression of nm23-H1; there was significant different NDPKA expression between transfected and non-transfected BcaCD885 cell lines; the invasion and metastases ability of transfected BcaCD885 cell lines decreased obviously.

CONCLUSIONnm23-H1 can inhibit the metastases of BcaCD885 cell lines significantly.

Cell Adhesion ; physiology ; Cell Movement ; physiology ; Genetic Vectors ; genetics ; Humans ; Monomeric GTP-Binding Proteins ; genetics ; metabolism ; Mouth Neoplasms ; genetics ; pathology ; physiopathology ; NM23 Nucleoside Diphosphate Kinases ; Nucleoside-Diphosphate Kinase ; Transcription Factors ; genetics ; metabolism ; Transfection ; Tumor Cells, Cultured

OBJECTIVETo identify molecular markers of lung squamous cell carcinoma by cDNA microarray technique.

METHODScDNA expression profiles were examined by microarrays of 6 surgical specimens of stage I lung squamous cell carcinomas. Those genes, either up-regulated or down-regulated in every specimen studied, were identified. The expression levels of nm23 and BRCA2 by the squamous cell carcinoma of the lung were further examined by immunohistochemical techniques.

RESULTSA total of 107 genes were identified, of which 26 were up-regulated and 81 were down-regulated in all six specimens. Immunohistochemical staining showed that, compared with normal lung tissues, the intensity of nm23 expression by the squamous cell carcinoma of lung was significantly increased while that of BRCA-2 was decreased.

CONCLUSIONcDNA microarrays can be used to identify gene expression profile of lung cancer, some of which may be used as markers of lung squamous cell carcinoma.

BRCA2 Protein ; metabolism ; Biomarkers, Tumor ; Carcinoma, Squamous Cell ; genetics ; metabolism ; Gene Expression Profiling ; Humans ; Lung Neoplasms ; genetics ; metabolism ; Male ; NM23 Nucleoside Diphosphate Kinases ; Nucleoside-Diphosphate Kinase ; metabolism ; Oligonucleotide Array Sequence Analysis

OBJECTIVE: To explore the relationship between the expressions of PTEN and the metastasis of the gallbladder cancer. METHODS: The expression of PTEN and nm23 were detected by immunohistochemical staining in 32 cases of gallbladder cancer with metastasis and the staining intensity was scored semi-quantitatively, compared with the cases without metastasis. RESULTS: The intensity score of PTEN and nm23 in gallbladder cancer with metastasis was 8.9947+/-4.5590 and 10.2003+/-3.9031, respectively, which was lower than that in those without metastasis (12.9433+/-4.7618 and 15.8436+/-5.6917 respectively, P < 0.01 ). The expression of PTEN was correlative with that of nm23 ( Pearson = 0.370, P < 0.05). CONCLUSION The lower expressions of PTEN and nm23 are related to the metastasis of gallbladder cancer.
Female ; Gallbladder Neoplasms ; metabolism ; Humans ; Liver Neoplasms ; metabolism ; secondary ; Lymphatic Metastasis ; Male ; NM23 Nucleoside Diphosphate Kinases ; Nucleoside-Diphosphate Kinase ; biosynthesis ; genetics ; PTEN Phosphohydrolase ; biosynthesis ; genetics ; Tumor Suppressor Proteins ; biosynthesis ; genetics

OBJECTIVETo understanding the molecular mechanisms in invasion and metastasis of the ovarian carcinoma, we investigate a novel candidate metastasis-associated gene (MTA1) and nm23H1 mRNA expression and mutation in ovarian carcinoma.

METHODSTwenty primary ovarian carcinoma specimens, 20 corresponding lymph nodes and 8 normal ovarian was examined for mRNA expression and mutation of MTA1 and nm23H1 genes by reverse-transcription polymerase chain reaction (RT-PCR) and RT-PCR-SSCP analysis. The level of the expression was determined by the relative optic density (ROD) of the PCR products.

RESULTSThe frequency of MAT1 overexpression was 100% (7/7) in primary ovarian carcinoma with metastasis but only 38.5% (5/13) in those without metastasis (P=0.0103). Overexpression of MAT1 was observed in 87.5% (6/7) of lymph nodes with metastasis but only 23% (3/13) of lymph nodes without metastasis (P=0.0118). In contrast with MAT1, low expression of nm23H1 mRNA was seen in 7 of 7 ovarian carcinoma with metastasis but only in 4 of 13 (30%) of those without metastasis (P=0.0043). Low nm23H1 expression was also seen in 7 of 7 lymph nodes with metastasis but only in 5 of 13 (38.5%) nonmetastatic lymph nodes (P=0.0102). The ROD ratio of MAT1 to nm23H1 increased with the development of metastasis. No mutation of MAT1 and nm23H1 genes was found by SSCP analysis.

CONCLUSIONThe mRNA expression of MTA1 and nm23H1 is positively and negatively correlated with lymph node metastasis, respectively. Expression abnormalities but not mutation of the two genes are frequent events related to lymph node metastasis of ovarian cancer.

Female ; Histone Deacetylases ; Humans ; Lymphatic Metastasis ; genetics ; Monomeric GTP-Binding Proteins ; biosynthesis ; genetics ; Mutation ; NM23 Nucleoside Diphosphate Kinases ; Neoplasm Invasiveness ; Neoplasm Proteins ; biosynthesis ; genetics ; Nucleoside-Diphosphate Kinase ; Ovarian Neoplasms ; genetics ; metabolism ; pathology ; RNA, Messenger ; genetics ; Repressor Proteins ; Transcription Factors ; biosynthesis ; genetics

OBJECTIVE: To investigate the expressions of Survivin protein and nm23 protein and the relationship among the expressions and axillary lymph node metastasis in breast cancer. METHODS: The expression of Survivin and nm23 in 80 cases of breast cancer tissues were detected by immunohistochemistry SP method, and their correlation with axillary lymph node metastasis and 5-year disease free survival (DFS) were analysed. RESULTS: Survivin protein positive expression rate was 68.75% (55/80) in breast cancer tissues, which had positive correlation with the axillary lymph nodes metastasis but negative correlation with 5 years FS (P < 0.05); nm23 protein expression had negative correlation with the axillary lymph nodes metastasis but positive to 5 years FS (P < 0.05). Survivin and nm23 proteins expression had no obvious correlation with the breast cancer pathology type, patient age and clinical stage (P > 0.05). CONCLUSION The anti-apoptosis effect of Survivin protein and the anti-metastasis effect of nm23 protein may be important in the occurrence and advancement of breast cancer, suggesting that it may be a new indicator of prognostic and judgement in breast cancer.
Adult ; Aged ; Axilla ; Biomarkers, Tumor ; Breast Neoplasms ; metabolism ; pathology ; surgery ; Female ; Humans ; Inhibitor of Apoptosis Proteins ; Lymph Nodes ; pathology ; Lymphatic Metastasis ; Mastectomy ; Microtubule-Associated Proteins ; biosynthesis ; genetics ; Middle Aged ; NM23 Nucleoside Diphosphate Kinases ; Neoplasm Proteins ; biosynthesis ; genetics ; Nucleoside-Diphosphate Kinase ; biosynthesis ; genetics ; Prognosis ; Retrospective Studies ; Survivin

OBJECTIVETo study the molecular mechanisms of nm23-H1 for regulating PKC signal pathway before and after transfection with nm23-H1 gene.

METHODSUsing Western-blot, Boyden-chamber, MTT and laser scanning confocal microscopy (LSCM) techniques to detect the distribution of PKC in cytosol and plasma membrane, changes of invasion and proliferation activity, PKC translocation status and changes of intracellular Ca(2+) concentration among different human pulmonary carcinoma cells with transfected or untransfected nm23-H1 gene, and changes of the three cell lines after treatment with Calphostin C, a PKC inhibitor.

RESULTS(1) The expression of PKCalpha, PKCbeta II on L9981 and L9981-pLXSN cell membrane, which was in activated status, was remarkably higher than those in L9981-nm23-H1 cell line (P < 0.001). The expression of PKCalpha, PKCbeta II in cytosol in L9981 and L9981-pLXSN cell lines, which was in inactivated status, was lower than those in L9981-nm23-H1 cell line (P < 0.001). It means that the PKC signal pathway was activated in L9981 and L9981-pLXSN cell lines. (2) PKCalpha and PKCbeta II mainly located in nuclei and perinuclear area in L9981 and L9981-pLXSN cells, which were in active status, and the Ca(2+) concentration in these cells was obviously higher than that in L9981-nm23-H1 cell line (P < 0.01). In L9981-nm23-H1 cell line, which was transfected with nm23-H1 gene, PKCalpha and PKCbeta II mainly located in soluble cytosolic section, in an inactive status. (3) The invasion and proliferation ability of L9981 and L9981-pLXSN lung cancer cells was higher than that of L9981-nm23-H1 cell line (P < 0.001). There was no statistically significant difference between L9981 and L9981-pLXSN cell lines (P > 0.05). (4) After treated with PKC inhibitor Calphstin C, the expression of PKC and PKCbeta II in membrane in L9981 and L9981-pLXSN cell lines was down-regulated (P < 0.001), PKCalpha and PKCbeta II were mainly located in cytosolic area, mainly in an inactive status, and the Ca(2+) concentration was found to be decreased in all the three cell lines. The invasion and proliferation ability of the three lung cancer cell lines were obviously decreasing (P < 0.001). However, the invasion and proliferation ability of L9981-nm23-H1 lung cancer cell line was still lower than that of L9981 and L9981-pLXSN lung cancer cell lines (P < 0.001). There was also no significant difference between L9981 and L9981-pLXSN cell lines (P > 0.05).

CONCLUSIONThe results of this study suggest that nm23-H1 gene might inhibit the invasion and metastasis of lung cancer cells by down-regulating PKC signaling pathway. The Ca(2+) in cells might be involved in this process.

Calcium ; metabolism ; Cell Line, Tumor ; Cell Membrane ; metabolism ; Cell Proliferation ; drug effects ; Cytosol ; metabolism ; Down-Regulation ; Humans ; Lung Neoplasms ; enzymology ; metabolism ; pathology ; NM23 Nucleoside Diphosphate Kinases ; genetics ; Naphthalenes ; pharmacology ; Neoplasm Invasiveness ; Protein Kinase C ; antagonists & inhibitors ; metabolism ; Protein Kinase C beta ; Protein Kinase C-alpha ; metabolism ; Signal Transduction ; Transfection

The metastasis-suppressing role of the nm23 gene in the metastatic spread of malignant tumor is still debated. We examined the nm23-H1 protein expression and gene mutation in non-Hodgkin's lymphomas to compare with the clinicopathologic parameters. The expression of nm23-H1 protein was immunohistochemically examined in 150 cases of non-Hodgkin's lymphomas; 85 diffuse large B cell lymphomas (DL-BCL), 18 marginal zone B cell lymphomas (MZL), 3 mantle cell lymphomas, 25 peripheral T cell lymphomas, not otherwise specified (TCLNOS), and 19 NK/T cell lymphomas (NK/T). Eighty-one cases (58 DLBCL, 6 MZL, 4 TCLNOS, and 13 NK/T) were studied for nm23-H1 gene mutation in exon 1 to 5. The high expression of nm23-H1 protein was associated with the high IPI score (p=0.019) and the low survival rate of the patients (p=0.0039). The gene mutation of nm23-H1 was detected in 10.3% of DLBCL and 30.7% of NK/T; but none in MZL and TCLNOS. The mutation was found in exon 1 in 5 cases, exon 2 in two cases, exon 4 in one case and both exon 1 and 2 in two cases. Our results suggest that the expression of nm23-H1 protein can be used as a poor prognostic marker in non-Hodgkin's lymphomas, and the mutational change of gene may operate in the lymphomagenesis.
Tissue Array Analysis ; Survival Analysis ; Prognosis ; Polymorphism, Single-Stranded Conformational ; Nucleoside-Diphosphate Kinase/*genetics/metabolism ; Mutation/*genetics ; Middle Aged ; Male ; Lymphoma, T-Cell/genetics/metabolism/pathology ; Lymphoma, Non-Hodgkin/genetics/metabolism/*pathology ; Lymphoma, Mantle-Cell/genetics/metabolism/pathology ; Lymphoma, Large-Cell, Diffuse/genetics/metabolism/pathology ; Lymphoma, B-Cell/genetics/metabolism/pathology ; Immunohistochemistry ; Humans ; Female ; DNA Mutational Analysis ; Base Sequence