Ps-61: Down-Regulation of The Genes Involved in Reprogramming (OCT4, SOX2, P21, ESC-specific microRNA miR-302 and miR-145) in Gastric Adenocarcinoma Reveals New Insight into Gastric Cancer

Khalili M *, Sadeghizadeh M , Alimoghaddam K , Malekzadeh R , Vasei M , Mowla Seyed J ,


Objective: Induced expression of a defined number of embryonic stem cell (ESCs)-specific genes, mainly OCT4 and SOX2, could reprogram a differentiated cell into an induced pluripotency stem (IPS) cell. The program is also inhibited by the action of some tumor suppressor genes, most importantly P53. There is a possibility that the re-expression of ips genes, i.e. OCT-4 and Sox2, and diminished expression of p53 and its main down-stream targets, i.e. P21 and miR-145, contributes also to tumorigenicity. Materials and Methods: A total number of 34 tumor and their matched non-tumor (as control) gastric surgical specimens were obtained. The expression and tissue distribution of the genes of interest were evaluated by means of real-time PCR and immunohistochemistry (IHC).The human embryonic carcinoma cell line, NTERA2 (NT2) and a human gastric adenocarcinoma cell line, AGS, were used as controls. Results: Our data revealed a significant down-regulation of P21 and miR-145 genes in tumor vs. non-tumor samples. The same finding was obtained for OCT4 variants, miR-302 and SOX2 expression in high-grade tumors. The ability of genes to discriminate tumor from non-tumor gastric samples was evaluated using the area under the receiver operating characteristic (ROC) curve. SOX2 showed the highest total area under the curve (AUC) (79%, p = 0.000). Although it found that the AUC for combination of miR-145 and p21 (71%, p=0.004) and all variants of OCT4 (75%, p = 0.008) has a better discrimination power than using each ones individually. In coordination to real-time PCR data, the results of immunohistochemistry for Sox2 protein showed the expression of Sox2 protein in tumor and non-tumor samples. Interestingly, despite the confirmation of OCT4A transcript expression in gastric tumor samples, we failed to detect any nuclear localization signal for Oct4 A protein in different grades of gastric tissue samples. Conclusion: Despite the fact that some hESC-specific genes are up-regulated in tumors, our data revealed down-regulation of miR-302b, OCT4 and SOX2 in high-grade tumors. So it suggests a specific regulatory role for these genes in the cell cycle control in the gastric samples. We also found that the expression of all genes are significantly vary between diffuse vs. intestinal as well as in high grade vs. low grade types of gastric tumor samples. Based on ROC curves, it seems that evaluation the expression of SOX2 individually and also miR-145 and P21 together are informative diagnostic tools for gastric tumors.