|
| Status |
Public on Sep 23, 2014 |
| Title |
Modulation of miR-29 Expression by Alpha-fetoprotein is linked to the Hepatocellular Carcinoma Epigenome |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by genome tiling array
|
| Summary |
Globally, hepatocellular carcinoma (HCC) accounts for 70-85% of primary liver cancers and ranks second in the leading cause of male cancer death. Serum alpha-fetoprotein (AFP), normally highly expressed in the liver only during fetal development, is reactivated in 60% of HCC tumors and associated with poor patient outcome. We hypothesize that AFP+ and AFP- tumors differ biologically. Using microarray-based global microRNA profiling in 223 HCC patients, we found that members of the miR-29 family were the most significantly (p<0.001) down-regulated miRNAs in AFP+ tumors. Consistent with miR-29's role in targeting DNA methyltransferase 3A (DNMT3A), a key enzyme regulating DNA methylation, we found a significant inverse correlation (p<0.001) between miR-29 and DNMT3A gene expression suggesting that they might be functionally antagonistic. Moreover, global DNA methylation array profiling reveals that AFP+ and AFP- HCC tumors have distinct global DNA methylation patterns and that increased DNA methylation is associated with AFP+ HCC. Interestingly, miR-29 family physiological expression is low in mouse embryonic livers but gradually increases after birth. This is in contrary to AFP expression, which dramatically decreases after birth. Experimentally, we demonstrated that increased AFP expression, or conditioned media from AFP expressing HCC cells, inhibits miR-29a expression in AFP- HCC cells. AFP also inhibited transcription of the miR-29a/b-1 locus and this effect is mediated through c-MYC binding to the miR-29a/b-1 promoter. Our findings indicate that tumor biology differs considerably between AFP+ HCC and AFP- HCC and that AFP is a functional antagonist of miR-29, which may contribute to global epigenetic alterations and poor prognosis in HCC.
|
| |
|
| Overall design |
Illumina Human BeadChip Methylation microarrays were completed on 48 tumor HCC tissues.
|
| |
|
| Citation(s) |
24798303 |
| Submission date |
Nov 01, 2013 |
| Last update date |
Jan 02, 2015 |
| Contact name |
Xin Wei Wang |
| E-mail(s) |
xw3u@nih.gov
|
| Phone |
240-760-6858
|
| Organization name |
National Cancer Institute
|
| Department |
Laboratory of Human Carcinogenesis
|
| Lab |
Liver Carcinogenesis Unit
|
| Street address |
37 Convent Drive
|
| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20892-4255 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL8490 |
Illumina HumanMethylation27 BeadChip (HumanMethylation27_270596_v.1.2) |
|
| Samples (48)
|
|
| Relations |
| BioProject |
PRJNA227378 |
Less...
More...