title: Modulation of miR-29 expression by α-fetoprotein is linked to the hepatocellular carcinoma epigenome.
abstract: Globally, hepatocellular carcinoma (HCC) accounts for 70%-85% of primary liver cancers and ranks as the second 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. Multivariable analysis in 237 HCC cases demonstrates that AFP level predicts poor survival independent of tumor stage (P<0.043). Using microarray-based global microRNA (miRNA) profiling, we found that miRNA-29 (miR-29) family members 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 profiling reveals that AFP+ and AFP- HCC tumors have distinct global DNA methylation patterns and that increased DNA methylation is associated with AFP+ HCC. Experimentally, we found that AFP expression in AFP- HCC cells induces cell proliferation, migration, and invasion. Overexpression of AFP, or conditioned media from AFP+ cells, inhibits miR-29a expression and induces DNMT3A 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 transcript of miR-29a/b-1. Furthermore, AFP expression promotes tumor growth of AFP- HCC cells in nude mice.
  
  
  CONCLUSIONS
  Tumor biology differs considerably between AFP+ HCC and AFP- HCC; AFP is a functional antagonist of miR-29, which may contribute to global epigenetic alterations and poor prognosis in HCC.
authors.affiliation: Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD; Tumor Biology Department, Georgetown University, Washington, DC.
authors.forename: Sonya
authors.initials: S
authors.lastname: Parpart
authors.forename: Stephanie
authors.initials: S
authors.lastname: Roessler
authors.forename: Fei
authors.initials: F
authors.lastname: Dong
authors.forename: Vinay
authors.initials: V
authors.lastname: Rao
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takai
authors.forename: Junfang
authors.initials: J
authors.lastname: Ji
authors.forename: Lun-Xiu
authors.initials: LX
authors.lastname: Qin
authors.forename: Qing-Hai
authors.initials: QH
authors.lastname: Ye
authors.forename: Hu-Liang
authors.initials: HL
authors.lastname: Jia
authors.forename: Zhao-You
authors.initials: ZY
authors.lastname: Tang
authors.forename: Xin Wei
authors.initials: XW
authors.lastname: Wang
mesh_terms: D000328:Adult; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics* / Q000401:mortality*; D045744:Cell Line, Tumor; D015331:Cohort Studies; D019175:DNA Methylation / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D015536:Down-Regulation / Q000235:genetics; D057890:Epigenomics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D000509:alpha-Fetoproteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D000509:alpha-Fetoproteins; D000090205:DNA Methyltransferase 3A