Central role of c-Myc during malignant conversion in human hepatocarcinogenesis.
Hepatocarcinogenesis is a multistage process in which precursor lesions progress into early hepatocellular carcinomas (eHCC) by sequential accumulation of multiple genetic and epigenetic alterations. To decode the molecular events during early stages of liver carcinogenesis, we performed gene expression profiling on cirrhotic (regenerative) and dysplastic nodules (DN), as well as eHCC. Although considerable heterogeneity was observed at the regenerative and dysplastic stages, overall, 460 differentially expressed genes were detected between DN and eHCC. Functional analysis of the significant gene set identified the MYC oncogene as a plausible driver gene for malignant conversion of the DNs. In addition, gene set enrichment analysis revealed global activation of the MYC up-regulated gene set in eHCC versus dysplasia. Presence of the MYC signature significantly correlated with increased expression of CSN5, as well as with higher overall transcription rate of genes located in the 8q chromosome region. Furthermore, a classifier constructed from MYC target genes could robustly discriminate eHCC from high-grade and low-grade DNs. In conclusion, our study identified unique expression patterns associated with the transition of high-grade DNs into eHCC and showed that activation of the MYC transcription signature is strongly associated with the malignant conversion of preneoplastic liver lesions.
Kaposi-Novak
Pal
P
Laboratory of Experimental Carcinogenesis, National Cancer Institute, Center for Cancer Research, NIH, Bethesda, Maryland 20892, USA.
Libbrecht
Louis
L
Woo
Hyun Goo
HG
Lee
Yun-Han
YH
Sears
Nathaniel C
NC
Coulouarn
Cedric
C
Conner
Elizabeth A
EA
Factor
Valentina M
VM
Roskams
Tania
T
Thorgeirsson
Snorri S
SS
D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics
C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc