| Esophageal cancer is malignancy of the esophagus which is the eighth most common cancer and the sixth most common cause of death from cancer worldwide. More than 80% of the cases and of the deaths occur in developing countries. Two types of esophageal cancer were identified based on pathological properties: esophageal adenocarcinoma(EAC) and esophageal squamous cell carcinoma(ESCC). Approximately 95% cases are esophageal squamous cell carcinoma worldwide. ESCC arises from the cells that line the upper part of the esophagus. EAC arises from glandular cells that are localized at the junction of the esophagus and stomach. The etiological agents of esophageal squamous cell carcinoma include hight temperature food, alcohol, tobacco and tension.MicroRNAs constitute a recently discovered family of endogenous short non-coding RNAs that negatively regulate gene expression by either translational inhibition or mRNA degradation. MicroRNAs recognize their targets based on sequence complementarity. The mature micorRNA is partially complementary to its target mRNAs. The complementary sites are usually localized witin the 3’untranslated region of the target mRNA. Malignant tumors and tumor cell lines were found to have widespread deregμlated microRNA expression profiles compared to normal tissues. Recent studies revealed that microRNA expression profiles that differ between normal esophageal cells, EAC and ESCC. However, downregulation of miR-100 has been found in both two type of esophageal cancer.There are no report about functions of miR-100 and its mechanisms so far. In the present studies, mi R-100 expression vector was constructed and transfected into esophageal squamous cell carcinoma cell line EC109. Cell lines with high expression of miR-100 were selected and used to figure out the biological functions of miR-100. We found that miR-100 was able to inhibit the proliferation of EC109 and induce cell cycle arrest at G1 phase. Moreover, our results showed that the overexpression of miR-100 inhibited cell migration and invasion and promoted cell apoptosis. Soft agar and xenograft transplantation experiments showed that miR-100 inhibited colony and tumor formation in vitro and in vivo. The targets of miR-100 was identified in our studies, luciferase and western-blot assay showed that CXCR7(CXC chemokine receptor 7) and FGFR3(fibroblast growth factor receptor 3) were both the direct targets of mi R-100.CXCR7 belongs to chemokine receptor family. The overexpression of CXCR7 has been identified in a veriaty of tumors such as lung cancer, breast cancer, prostate cancer and hepatocellular carcinoma. It has been shown that overexpression of CXCR7 enhanced cell migration, proliferation and promoted tumor growth in animal models. Two ligands bind to CXCR7, named CXCL11 and CXCL12. Activation of CXCR7 by CXCL12 induced trans-endothelial migration. Moreover, CXCL12 expression was associated with overall and disease-free survival in pancreas carcinoma, suggesting that CXCL12 is the predominant ligand associated with CXCR7-mediated metastasis formation. FGFR3 is a member of the fibroblast growth factor receptor family, which is a transmembrane protein that consists of an extracellular region with three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. Activation of FGFR3 by its ligands promotes a cascade of downstream signals which play a role in several important cellular processes, including regulation of cell growth and division, formation of blood vessels, wound healing and embryo development. Activation of the fibroblast growth factor receptor pathway is a common event in many cancer types. The activation of FGF signalling in cancer results in promoting cancer cell proliferation, survival and migration.Taken together, our studies showed that miR-100 may inhibit cell growth, migration, invasion and tumor formation through targeting CXCR7 and FGFR3, indicating a great potential for miRNA-based therapy against esophageal cancer. |
