Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer.
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.
Grady
W M
WM
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Parkin
R K
RK
Mitchell
P S
PS
Lee
J H
JH
Kim
Y-H
YH
Tsuchiya
K D
KD
Washington
M K
MK
Paraskeva
C
C
Willson
J K V
JK
Kaz
A M
AM
Kroh
E M
EM
Allen
A
A
Fritz
B R
BR
Markowitz
S D
SD
Tewari
M
M
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*
D015815:Cell Adhesion Molecules; D004273:DNA, Neoplasm; C484449:EVL protein, human; D035683:MicroRNAs