The nm23-H1 gene is known as a potential metastasis suppressor gene in various types of carcinomas. However, the role of nm23-H1 in colorectal carcinoma still remains controversial and the cellular mechanisms by which its protein may modulate the metastatic phenotype are not yet known. We transfected nm23-H1 cDNA into the human colon cancer cell line, HT-29, to test the effects and cellular biological mechanism of nm23 protein in colon cancer. We found that nm23-H1 strongly inhibited the liver metastasis of HT-29 cells in nude mice and inhibited the epidermal growth factor (EGF)-induced cell migration in vitro. The nm23 gene was first identified as a gene whose expression was reduced in highly metastatic rodent tumors relative to poorly metastatic tumor cells. 1 The transfection of nm23 cDNA into various cancer cell lines resulted in the suppression of metastatic potential of motility, invasion or colonization. [2][3][4][5][6][7] This implies that nm23 is a potential metastasis suppressor gene and could function on the invasion and migration steps of the metastatic pathway. The nm23 protein has a kinase activity and is recognized as a nucleoside diphosphate (NDP) kinase. Eight human nm23 genes have been characterized so far. The initial 4 human genes of this family, nm23- H1,) and nm23-H4, encode proteins products that process NDP kinase activity and are named NDP kinase A-D, respectively. Of the 8 human nm23 genes, the H1 gene is most closely correlated with the metastatic phenotype in human breast, colorectal and ovarian carcinoma. 8 -12 However, the role of nm23-H1 in colorectal carcinoma is still controversial. Conflicting observations have been reported. Allelic deletion or mutation of the nm23-H1 gene appears to be associated with distant metastasis in some studies; 13-16 on the other hand, there are several studies that denied the correlation between the progression of colorectal carcinogenesis or distant metastasis and nm23-H1 expression. [17][18][19] The cellular mechanisms by which the nm23-H1 protein may directly or indirectly modulate the metastatic phenotype are not yet known; however, several studies reported that nm23-H1 inhibited the cell motility toward polypeptide growth factors such as platelet derived growth factor (PDGF) and insulin-like growth factor (IGF). 20,21 Among those growth factor receptors, the epidermal growth factor receptor (EGFR) is one of the receptors most commonly associated with human tumors and has been shown to correlate with the progression of many types of tumors, 22,23 and it is associated with the aspects of tumor growth (i.e., proliferation, apoptosis and cell survival). However, it has been reported that EGF stimulated the migration of both normal and tumor cells. 24 -27 Furthermore, it has been reported that mitogen-activated protein kinase (MAPK) (ERK1 and ERK2) influenced the cellular motility mechanism by phosphorylating and thereby enhanced myosin light chain kinase (MLCK) activity leading to the phosphorylation of myosin light chains (MLC). 28 In our study...

EXO1 is a member of the RAD2 nuclease family and functions in DNA replication, repair and recombination. We investigated the relationship of single nucleotide polymorphisms (SNPs) at exon 10 (T439M) and exon 13 (P757L) of the EXO1 gene with development, progression and metastasis of colorectal cancer. For T439M, the Thr/Met genotype [odds ratio (OR) = 2.03, 95% confidence interval (CI) 1.04-3.98] and Thr/Met and Met/Met genotypes combined (OR = 2.37, 95% CI 1.23-4.56) demonstrated significant association with the development of colorectal cancer after adjusting for age, gender and smoking status. For P757L, patients with the Leu/Leu genotype showed a reduced risk of colorectal cancer (adjusted OR = 0.398, 95% CI 0.183-0.866) when the Pro/Leu and Pro/Pro genotypes were combined and used as the reference. The Leu/Leu genotype also had a reduced risk (adjusted OR = 0.373, 95% CI 0.164-0.850) when the Pro/Leu genotype was used as the reference. Individuals who carried both putative risk genotypes (Thr/Met and Met/Met for T439M and Pro/Leu for P757L) showed an adjusted OR of 4.95 (95% CI 1.56-15.7) compared with those who carried both low risk genotypes. Analysis of microsatellite instability (MSI) revealed that tumors from individuals who carried both putative risk genotypes tended to have a higher frequency of MSI positives than those from patients who carried both low risk genotypes, although a significant correlation was not found between EXO1 genotype and MSI status. This is the first report to provide evidence for an association of EXO1 gene polymorphisms with colorectal cancer risk. The EXO1 genotypes were not associated with any clinicopathological characteristics in colorectal cancer patients.

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Summary Over-expression of erbB-2 is associated with shortened survival of patients with lung adenocarcinomas. We demonstrated that human lung epithelial cells, overexpressing erbB-2, formed tumours in nude mice only when high levels of transforming growth factor (TGF)-a were produced (E6T cells). To define the role that TGF-a production played in induction of tumorigenicity, a non-tumorigenic TGF-a-negative clone of ErbB-2 overexpressing cells (E2 cells) was transfected with an expression vector for TGF-a (E2a cells). Transfected clones produced TGF-a at 11-25% of the level produced by the E6T cell line. Tumorigenic E6T cells transfected with a TGF-a antisense vector (E6TA cells) expressed only 6% of the TGF-a level of the parental cells. Clones of E6T, E6TA, E2 and E2a were inoculated into athymic nude mice to measure tumorigenic potential. E6T cells formed tumours with a 70% efficiency. E2, E6TA and E2a cells failed to form tumours. The levels of EGFR were similar in non-tumorigenic E2 and tumorigenic E6T cells but higher in E2a and E6TA cells, and ErbB-2 were greatly overexpressed in an E2a clone. In vitro, ErbB-2 co-immunoprecipitated with EGFR in lysates of unstimulated E6T and E2a TGF-a-producing cells, indicating that the lower TGF-a levels were sufficient to induce in vitro heterodimerization. These studies suggest that induction of the tumorigenic phenotype depends on achieving a threshold level of TGF-a sufficient to activate downstream signalling by ErbB-2 containing active heterodimers.

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