Mounting evidence suggests that OPN plays a role in the regulation of tumor metastasis and that OPN expression is particularly high in metastatic tumors . OPN is overexpressed in cancers that have a high propensity for forming bone metastases. In bone metastases, OPN is generally associated with the interface between the carcinoma and the bone surface, and this appears to be related to increased bone resorptive activity by osteoclasts . Moreover, high OPN expression in the primary tumor is associated with early metastasis and poor clinical outcome in human gastric cancer and other cancers [24–27].
A recent study suggested that the OPN promoter was associated with NSCLC . In the present study, we focused on the association of these SNPs with GC, and although the distribution of genotypes in the OPN promoter was not significantly different between GC patients and healthy controls, there were significant differences in the distribution of genotypes (CC) at nt -443 between patients with stage IV and stage I gastric cancer (IA + IB) and between stage IV and the combined other three stages of gastric cancer (IA + IB + II + III; Table 4). The survival rates for patients with the C/C genotype were significantly lower than the survival rates of the other two genotypes (C/T, T/T; Figure 3). In addition, significantly higher luciferase activities were generated with the pGL3-C construct compared to the pGL3-T construct. Reporter gene analysis has shown that the haplotype -443C/-156 G/-66 T is associated with significantly enhanced promoter activity compared to five other allelic variants tested . A recent study on melanoma metastases found that those homozygous for the -443C allele expressed significantly higher levels of OPN mRNA compared to those that were either heterozygous (CT) or homozygous for the -443 T allele . Transcription factor c-Myb binds to the region of the OPN promoter in an allele-specific manner and induces enhanced activity of the -443C compared to the -443 T OPN promoter . Taken together, these data suggest that the variation at nt -443 in the OPN promoter plays a role in GC progression and metastasis, especially for the CC genotype at nt -443 in the OPN promoter. Whether the polymorphisms of OPN is related to expression of OPN in cancer patients remain unknown although. Over-expression of OPN was found in gastric cancer samples in a previous study . Therefore, additional studies are needed to further elucidate this finding.
In the present study, we found that the CT genotype at nt -443 in the OPN promoter showed significant differences between stage IV and stage II gastric cancer, and also between stage IV and other stages of gastric cancer (IA + IB + II + III), but not between stage IV and stage III or stage I. The main reason for this may be due to the limited number of patients in each subgroup. It is also possible that the transcription factor c-Myb might have enhanced the activity of the region of the OPN promoter that contained the CC or CT genotypes, but not the other genotype (i.e., TT) . However, these hypotheses require further investigation in larger studies.
The present genomic findings in healthy controls were not identical to previous findings among Japanese and Italian control subjects [30, 31]. Although previous reports suggest that high OPN is expressed at high levels in GC , we found no association between the genotypes of the OPN promoter with the risk of GC. However, we have found ethnic differences in SNPs of several host genes in GC patients [30, 31]. Therefore, the present findings may not apply to all populations. Nonetheless, although there was no association between OPN SNPs and GC gastric cancer susceptibility or severity in Chinese patients, our findings do suggest that there is an association with metastasis of GC.