title: Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer.
abstract: MicroRNAs are small, non-coding RNAs that influence gene regulatory networks by post-transcriptional regulation of specific messenger RNA targets. MicroRNA expression is dysregulated in human malignancies, frequently leading to loss of expression of certain microRNAs. We report that expression of hsa-miR-342, a microRNA encoded in an intron of the gene EVL, is commonly suppressed in human colorectal cancer. The expression of hsa-miR-342 is coordinated with that of EVL and our results indicate that the mechanism of silencing is CpG island methylation upstream of EVL. We found methylation at the EVL/hsa-miR-342 locus in 86% of colorectal adenocarcinomas and in 67% of adenomas, indicating that it is an early event in colorectal carcinogenesis. In addition, we observed a higher frequency of methylation (56%) in histologically normal colorectal mucosa from individuals with concurrent cancer compared to mucosa from individuals without colorectal cancer (12%), suggesting the existence of a 'field defect' involving methylated EVL/hsa-miR-342. Furthermore, reconstitution of hsa-miR-342 in the colorectal cancer cell line HT-29 induced apoptosis, suggesting that this microRNA could function as a proapoptotic tumor suppressor. In aggregate, these results support a novel mechanism for silencing intronic microRNAs in cancer by epigenetic alterations of cognate host genes.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: W M
authors.initials: WM
authors.lastname: Grady
authors.forename: R K
authors.initials: RK
authors.lastname: Parkin
authors.forename: P S
authors.initials: PS
authors.lastname: Mitchell
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.forename: Y-H
authors.initials: YH
authors.lastname: Kim
authors.forename: K D
authors.initials: KD
authors.lastname: Tsuchiya
authors.forename: M K
authors.initials: MK
authors.lastname: Washington
authors.forename: C
authors.initials: C
authors.lastname: Paraskeva
authors.forename: J K V
authors.initials: JK
authors.lastname: Willson
authors.forename: A M
authors.initials: AM
authors.lastname: Kaz
authors.forename: E M
authors.initials: EM
authors.lastname: Kroh
authors.forename: A
authors.initials: A
authors.lastname: Allen
authors.forename: B R
authors.initials: BR
authors.lastname: Fritz
authors.forename: S D
authors.initials: SD
authors.lastname: Markowitz
authors.forename: M
authors.initials: M
authors.lastname: Tewari
mesh_terms: D017209:Apoptosis; D015815:Cell Adhesion Molecules / Q000235:genetics*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007438:Introns; D035683:MicroRNAs / Q000235:genetics*
chemical_list: D015815:Cell Adhesion Molecules; D004273:DNA, Neoplasm; C484449:EVL protein, human; D035683:MicroRNAs