Colorectal Cancer
Copyright ©2006 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Nov 28, 2006; 12(44): 7113-7117
Published online Nov 28, 2006. doi: 10.3748/wjg.v12.i44.7113
Hypermethylation and expression regulation of secreted frizzled-related protein genes in colorectal tumor
Jian Qi, You-Qing Zhu, Jun Luo, Wen-Hui Tao
Jian Qi, You-Qing Zhu, Wen-Hui Tao, Department of Gastroenterology, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei Province, China
Jun Luo, Department of Pathology, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei Province, China
Supported by the Special-purpose Scientific Research Foundation for University Doctorate Project of the Ministry of Education of China, No. 301090255
Correspondence to: Dr. You-Qing Zhu, Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei Province, China. uqing_zhu@sina.com
Telephone: +86-27-87336141
Received: August 25, 2006
Revised: August 28, 2006
Accepted: September 18, 2006
Published online: November 28, 2006
Abstract

AIM: To investigate the functions of promoter hyper-methylation of secreted frizzled-related proteins (sFRPs) genes in colorectal tumorigenesis and progression.

METHODS: The promoter hypermethylation and expression of sFRP genes in 72 sporadic colorectal carcinomas, 33 adenomas, 18 aberrant crypt foci (ACF) and colorectal cancer cell lines RKO, HCT116 and SW480 were detected by methylation-specific PCR and reverse transcription PCR, respectively.

RESULTS: None of the normal colorectal mucosa tissues showed methylated bands of any of four sFRP genes. sFRP1, 2, 4 and 5 were frequently methylated in colorectal carcinoma, adenoma and ACF (sFRP1 > 85%, sFRP2 >75%, sFRP5 > 50%), and the differences between three colorectal tissues were not significant (P > 0.05). Methylation in colorectal tumors was more frequent than in normal mucosa and adjacent normal mucosa. The mRNA of sFRP1-5 genes was expressed in all normal colorectal mucosa samples. Expression of sFRP1, 2, 4 and 5 and sFRP1, 2 and 5 was downregulated in carcinoma and adenoma, respectively. The downregulation of sFRP2, 4 and 5 was more frequent in carcinoma than in adenoma. Expression of sFRP3 which promoter has no CpG island was downregulated in only a few of colorectal tumor samples (7/105). The downregulation of sFRP1, 2, 4 and 5 expression was significantly associated with promoter hypermethylation in colorectal tumor. After cells were treated by DAC/TSA combination, the silenced sFRP mRNA expression could be effectively re-expressed in colorectal cancer cell lines.

CONCLUSION: Hypermethylation of sFRP genes is a common early event in the evolution of colorectal tumor, occurring frequently in ACF, which is regarded as the earliest lesion of multistage colorectal carcinogenesis. It appears to functionally silence sFRP genes expression. Methylation of sFRP1, 2 and 5 genes might serve as indicators for colorectal tumor.

Keywords: Colorectal tumor; Secreted frizzled-related protein genes; Methylation; Indicator; Re-expression