Aberrant Expression And Its Mechanism Of SFRP4-the Antagonists Of Wnt In Pancreatic Carcinoma

ObjectiveThe canonical Wnt signaling pathway takes important roles in embryonic development,cell proliferation and cell differentiation. Defects in this pathway have been implicated in the pathogenesis of various types of tumors in human beings. Secreted frizzled-ralated proteins(SFRPs) are a family of Wnt antagonists that habours a cyteine-rich domain(CRD) homologous to the frizzled receptors. SFRPs are able to bind Wnt proteins in the extracellular compartment,thereby inhibiting ligand-receptor interaction and signal transduction.SFRP4 is a putative inhibitor of Wnt signaling. Its expression is frequently lost or strongly reduced in some tumors.,including breast,colorectal,prostate and ovarian cancers. The SFRP4 gene is located in a chromosomal region that is frequently deleted in some tumors and is thought to harbour a tumor suppressor gene. To be a member of SFRPs family, some studies indicated that silencing of SFRP4 expression played an important role in the carcinogenesis of esophagus and colorectal tumors.In this study, we aim to investigate the expressions of SFRP4 in pancreatic tumors and matched normal pancreatic tissues,analyze the mechanism of gene silencing. Meanwhile, analyze the relationship between the aberrant expression and clinical pathologic characteristics.Materials and MethodsMatched tumor/normal samples of pancreatic cancer specimens(n=36) analyzed in the study were obtained from patients at the departments of general surgeny at second affliated hospital,China medical university between 2005 and 2006, and three human pancreatic cancer cell lines purchased from shanghai kunken biochemistry company. We detected the protein expression of SFRP4 with immunohistochemiccal method,detected the level of mRNA with RT-PCR method, and the status of methelation with the methelation-specific PCR method. The clinical pathologic characteristics of all patients were summarized to find the rationship between the loss of expression of the both genes and their clinical pathologic characteristics.ResultsIn three human pancreatic cell lines, two of them the SFRP4 mRNA expression silence were discovered. After the process of demethelation in the two cell lines,the SFRP4 mRNA recover again. The loss of SFFRP4 expression was detected in 15 pancreatic cancer samples. In matched normal tissues, the loss of expression occurred in 3 samples. The difference between cancer and match normal tissue is significant. Methylation of SFRP4 promoter was found in 17 pancreatic cancer samples and in 5 matched normal tissues. The different between cancer and matched normal tissue is significant. The loss of SFRP4 expression is correlated with status of methylation , TNM stages and lymph node metastasis of tumors.Conclusion1. The loss of SFRP4 expression may take place in pancreatic cancer tissue mostly, the machenism is due to the methelation of promoter.2. The loss of SFRP4 expression may be correlated with the greater invasive capacity of the cancer and associated with unfavorable prognosis.3. The loss of SFRP4 expression may be linked to the occurrence of partial pancreatic cancer.