Integrative and comparative genomics analysis of early hepatocellular carcinoma differentiated from liver regeneration in young and old.
BACKGROUND
Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related deaths worldwide. It is often diagnosed at an advanced stage, and hence typically has a poor prognosis. To identify distinct molecular mechanisms for early HCC we developed a rat model of liver regeneration post-hepatectomy, as well as liver cells undergoing malignant transformation and compared them to normal liver using a microarray approach. Subsequently, we performed cross-species comparative analysis coupled with copy number alterations (CNA) of independent early human HCC microarray studies to facilitate the identification of critical regulatory modules conserved across species.


RESULTS
We identified 35 signature genes conserved across species, and shared among different types of early human HCCs. Over 70% of signature genes were cancer-related, and more than 50% of the conserved genes were mapped to human genomic CNA regions. Functional annotation revealed genes already implicated in HCC, as well as novel genes which were not previously reported in liver tumors. A subset of differentially expressed genes was validated using quantitative RT-PCR. Concordance was also confirmed for a significant number of genes and pathways in five independent validation microarray datasets. Our results indicated alterations in a number of cancer related pathways, including p53, p38 MAPK, ERK/MAPK, PI3K/AKT, and TGF-beta signaling pathways, and potential critical regulatory role of MYC, ERBB2, HNF4A, and SMAD3 for early HCC transformation.


CONCLUSIONS
The integrative analysis of transcriptional deregulation, genomic CNA and comparative cross species analysis brings new insights into the molecular profile of early hepatoma formation. This approach may lead to robust biomarkers for the detection of early human HCC.
Colak
Dilek
D
Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. dcolakkaya@kfshrc.edu.sa
Chishti
Muhammad A
MA
Al-Bakheet
Al-Bandary
AB
Al-Qahtani
Ahmed
A
Shoukri
Mohamed M
MM
Goyns
Malcolm H
MH
Ozand
Pinar T
PT
Quackenbush
John
J
Park
Ben H
BH
Kaya
Namik
N
D000375:Aging / Q000235:genetics*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation; D018628:Gene Dosage; D020869:Gene Expression Profiling; D023281:Genomics; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D008115:Liver Regeneration; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction