Epigenetically regulated MIR941 and MIR1247 target gastric cancer cell growth and migration.
Altered expression of microRNA (miRNA) can significantly contribute to cancer development and recent studies have shown that a number of miRNAs may be regulated by DNA methylation. Through a candidate gene approach, we identified MIR941 and MIR1247 to be transcriptionally silenced by DNA hypermethylation in several gastric cancer cell lines. We confirmed that these miRNAs are also densely methylated in primary gastric cancers but not in normal gastric tissues. In addition, we demonstrated that ectopic expression of these two miRNAs in AGS gastric cancer cells resulted in suppression of growth and migration. Furthermore, we tested genes predicted to be the targets of MIR941 and MIR1247 and identified 7 and 6 genes, whose expressions were significantly downregulated by transfection of MIR941 and MIR1247 mimics, respectively, in gastric cancer cell lines. Some of these genes are known to promote proliferation and invasion, phenotypes we observed upon ectopic expression of the two miRNAs. Thus, we examined these candidates more closely and found that downregulation of mRNA corresponded to a decrease in protein levels (observed by western blot). Our study provides unequivocal evidence that MIR941 and MIR1247 are transcriptionally regulated by DNA methylation in gastric cancer and that they have tumor suppressor properties through their inhibition of key cancer promoting genes in this context.
Research Center; Dongnam Institute of Radiological & Medical Sciences (DIRAMS); Busan, South Korea.
Joong-Gook
JG
Kim
Department of Internal Medicine; Inje University Haeundae Paik Hospital; Busan, South Korea.
Tae-Oh
TO
Kim
Research Center; Dongnam Institute of Radiological & Medical Sciences (DIRAMS); Busan, South Korea.
Jin-Han
JH
Bae
Research Center; Dongnam Institute of Radiological & Medical Sciences (DIRAMS); Busan, South Korea.
Jae-Woong
JW
Shim
Department of Internal Medicine; Inje University Haeundae Paik Hospital; Busan, South Korea.
Myoung Joo
MJ
Kang
Research Center; Dongnam Institute of Radiological & Medical Sciences (DIRAMS); Busan, South Korea.
Kwangmo
K
Yang
Genomic Medicine Institute; Lerner Research Institute; Cleveland Clinic Foundation; Cleveland, OH USA.
Angela H
AH
Ting
Research Center; Dongnam Institute of Radiological & Medical Sciences (DIRAMS); Busan, South Korea.
Joo Mi
JM
Yi
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000236:Adenoma / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*
D035683:MicroRNAs; D012333:RNA, Messenger
5-aza-2'-deoxycytidine; DNA methylation; MIR1247; MIR941; epigenetics; gastric cancer; microRNA