The Study On The Relationship Between Reprimo, S100A2 With Primary Gastric Adenocarcinoma

Research background:The primary gastric carcinoma (GC) is one of the most common malignancies in China.170,000 patients died from gastric carcinoma, accounting for about one-fourth of all cancer death, and 200,000 new cases are diagnosed annually. Surgery is currently the main choice of therapy for gastric carcinoma, however, for most patients with gastric carcinoma, the tumor is discovered too late to make surgery helpful. Although the treatments such as surgical operation, chemotherapy, radiotherapy, and interventional therapy have shown some benefit for the patients, they can not improve the 5 year survival rate. Gastric cancer is a curable disease if diagnosed at early stage. However, most cases are diagnosed at advanced stage because of the lack of screening programs. Therefore, developing novel diagnostic markers should provide not only a better understanding the molecular mechanism of carcinogenesis, progression, and metastasis, but also may promote new strategies for therapeutic targets in gastric cancer.Objectives and methods:In this retrospective study, the protein expressions of Reprimo and S100A2 were evaluated by immunohistochemistry, and the DNA methylation status of the Reprimo promoter were examined by methylation specific PCR (MSP) from surgical specimens of primary gastric adenocarcinoma, high grade gastric intraepithelial neoplasias, low grade gastric intraepithelial neoplasias and normal gastric mucosa tissues. We also assessed the relationship between Reprimo and S100A2 protein expression and clinicopathologic findings of gastric cancer. Moreover, the association between methylation and expression of Reprimo was also investigated in those tissues. The purposes of this study were to explore:(1) the correlation between Reprimo, S100A2 and the occurrence, development, invasion, metastasis of tumor and their possible interactions, so as to offer prognostic predictors for this tumor.(2) the correlation between Reprimo methylation and occurrence, development of GC, so as to find early diagnosis marker of this cancer.Results:1. The positive rates of Reprimo and S100A2 were as follows:Reprimo (100%,80%,36.67%,35%), S100A2 (100%,86.67%,46.67%,48%) in normal gastric mucosa tissues, low grade gastric intraepithelial neoplasias, high grade gastric intraepithelial neoplasias and GC tissues, respectively. Statistical analysis revealed higher expression of Reprimo and S100A2 in normal and low grade intraepithelial neoplasias tissues than that in high grade intraepithelial neoplasias and cancer tissues. However, there was no difference between high grade intraepithelial neoplasias and cancer tissues.2. Reprimo positive stainning was uncorrelated with tumor differentiation, however, S100A2 positive stainnig was correlated with tumor differentiation. Both Reprimo and S100A2 positive stainning were correlated with tumor depth of invasion and lymph node mentastasis. 3. There was a striking association between the expressions of Reprimo and S100A2.4. Reprimo Promoter hypermethylation were found in 0% of normal gastric tissues,6.67%(1/15) of low grade intraepithelial neoplasias,37.50%(6/16)of high grade intraepithelial neoplasias and 66.67 (32/48) of gastric adenocarcinomas. Statistical analysis revealed that Reprimo methylated bands were higher in cancer tissues than that in high grade intraepithelial neoplasias, low grade intraepithelial neoplasias tissue and normal tissues.5. There was no correlation between Reprimo methylation status and tumor differentiation, depth of invasion, as well as lymph node mentastasis.6.The positive rates of Reprimo expression was only 31.25% in 32 methylated cases, but 62.50% in 16 cases without methylated bands. There was a striking correlation between the promoter methylation and negative expressions of Reprimo.Conclusions:1. Reprimo and S100A2 positive stainning rates were higher in low grade intraepithelial neoplasias, normal tissues than that in high grade intraepithelial neoplasias and GC tissues, which indicated that Reprimo and S100A2 expressions were associated with the occurrence and development of GC. Reprimo and S100A2 positive stainning were correlated with tumor depth of invasion and lymph node mentastasis groups. The higher positive expressions of Reprimo and S100A2 could suppress the invasion and metastasis ability of GC. The loss expression of Reprimo and S100A2 always indicate higher invsion and metastasis potention and poor prognosis of gastric adenocarcinoma. Combined detection of Reprimo and S100A2 may be helpful to evaluate malignant degree and predict the prognosis of this cancer. 2. Reprimo and S100A2 could play dependent roles in the occurrence and development of GC.3. Promoter hypermethylation of Reprimo gene frequently occurs during gastric carcinogenesis, and may contribute to cancer development. It might be a potential candidate for early detection of gastric cancer. 4.There was an especially statistical significance in the correlation between Reprimo expression and its promoter methylation. Loss or down-expression of Reprimo was associated with its promoter hypermethylation in GC.