title: Aberrant methylation of the PTCH1 gene promoter region in aberrant crypt foci.
abstract: Patched homolog 1 (PTCH1) is a known tumor suppressor that regulates the Hedgehog (Hh) pathway and has been implicated in tumorigenesis. The role of PTCH1 in colon carcinogenesis, however, is controversial. The aim of the present study was to investigate epigenetic modifications of PTCH1 in aberrant crypt foci (ACF), the earliest precursor lesion of colorectal cancer (CRC). Using laser-capture microdissection (LCM), a pure population of ACF epithelial cells was isolated and studied. The inherent protein expression levels of SHH, PTCH1, SMO and GLI1 were assessed by immunohistochemistry for 405 ACF, including 54 dysplastic ACF (d-ACF) and 351 non-dysplastic ACF (n-ACF). The mRNA levels and methylation status of PTCH1 were also determined in 54 d-ACF and 96 n-ACF. Our data showed that the expression of SHH, SMO and GLI1 was significantly up-regulated in d-ACF, compared to n-ACF. Also, the mRNA and protein levels of PTCH1 were lower in d-ACF than n-ACF. Using MSP or MS-HRM, PTCH1 methylation was present in 64.8% (35/54) or 63.3% (34/54), respectively, of d-ACF and 19.8% (19/96) or 22.9% (11/48), respectively, of n-ACF. PTCH1 methylation was more frequent in d-ACF than n-ACF (p < 0.001) and was associated with PTCH1 mRNA levels (r = 0.358, p < 0.01). There was a statistically significant correlation between PTCH1 methylation status and the prevalence of colorectal neoplasms. In conclusion, this study suggests that aberrant methylation of the PTCH1 promoter may be an early, initiating event of colon carcinogenesis.
authors.affiliation: Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
authors.forename: Jingjing
authors.initials: J
authors.lastname: Hu
authors.forename: Shujun
authors.initials: S
authors.lastname: Li
authors.forename: Zhongqiu
authors.initials: Z
authors.lastname: Wang
authors.forename: Bingqing
authors.initials: B
authors.lastname: Xia
authors.forename: Bo
authors.initials: B
authors.lastname: Jiang
authors.forename: Bingsheng
authors.initials: B
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Xinying
authors.initials: X
authors.lastname: Wang
mesh_terms: D058739:Aberrant Crypt Foci / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D061346:Laser Capture Microdissection; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D055815:Young Adult; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C509239:SHH protein, human; C491023:SMO protein, human; D000072086:Smoothened Receptor; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1