Wnt Antagonist SFRP1 In Colorectal Tumorigenesis

Objective To investigate the expressions of SFRP1 in matched normal large bowel mucosal samples, colorectal adenoma samples and colorectal cancer samples. To analyze the mechanism of gene silencing. To assess the functional change of SFRP1 ,in colorectal tumorigenesis, analyze the relationship between the aberrant expression and clinical pathologic characteristics.Methods We conducted immunohistochemical investigation,Analysis of Promoter Methylation Status (MSP) and semiquantitatively determined with reverse transcription-polymerase chain reaction (RT-PCR)to SFRP1,E-cad,β-cat,c-myc,cyclinD1 in matched normal large bowel mucosal samples, colorectal adenoma samples and colorectal cancer samples. The relationship of the methylation status with the expression of relevant protein was analysed. The relationship of the methylation status and the expression of protein with the biological behavior of colorectal cancer was analysed.Results1 .RT-PCR Compared to control groups,the expression of SFRP₁ mRNA in colorectal adenomas and colorectal cancer are downregulated(P< 0.05),and the expression of SFRP₁ mRNA in colorectal adenomas is lower than in colorectal cancer(P< 0.05).2.Immunohistochemistryβ-cat and E-cad were deleted in different degrees when they were observed in colorectal adenomas and colorectal cancer.β-cat had ectopic expression in cytoplasm and cellular nucleus, and its rate was lower in colorectal adenomas than in colorectal cancer (87.5%,100%, respectively, P< 0.05). The depletion rates ofβ-cat and E-cad in colorectal adenoma samples (37.5%,37.5 % respectively)were lower than in colorectal cancer samples (58.8%,76.4% respectively, P< 0.05) . Abnormal expression rates of c-myc and cyclinD1 in colorectal adenoma were lower samples than in colorectal cancer samples.3. MSP The methylation status of SFRP1 promtor region in 165 matched normal large bowel mucosal samples and 80 colorectal adenoma samples all were 0.00%, and 25.88%(22/85) in colorectal cancer. Methylation of the SFRP1 promotor region was increased in colorectal cancer samples.Conclusions1 The inactivation and down-regulation of SFRP1 observed are consistent with its acting as a tumor suppressor gene in colorectal tumorigenesis, which lead to the aberrant expressions ofβ-cat,E-cad,c-myc,cyclinD1.Furthermore , investigation of the methylation status of the promotor region of SFRP1 by methylationspecific PCR revealed hypermethylation in 22 colorectal cancers.2 These data demonstrate that hypermethylation of the SFRP1 promoter region is a frequent event in colorectal cancer and is increased significantly compared with normal mucosa from the same patient. But there was not an absolute inverse correlation between methylation and transcription. Our results show that methylation and transcriptional repression are common events in colorectal cancer and this may influence the role of SFRP1 in tumorigenesis. Our findings clearly demonstrate the function of SFRP1 in colorectal carcinogenesis,and we can participateif we treat with a demethylating agent for the colon cancers which have SFRP1 promter methylation, demethylation of the promoter and re-expression of SFRP1 could be observed.3 So we can detect hypermethylation of the SFRP1 promoter region to prognose colon cancers. Perhaps taking this method to colon cancers which, we can prevent and cure colon cancers. Because SFRP1 regulates a wide spectrum of Wnt activities and pathways, these results suggest that regulating Wnt pathways plays a significant role in colorectal carcinogenesis.