|Budget Amount *help
¥111,540,000 (Direct Cost : ¥85,800,000、Indirect Cost : ¥25,740,000)
Fiscal Year 2006 : ¥18,980,000 (Direct Cost : ¥14,600,000、Indirect Cost : ¥4,380,000)
Fiscal Year 2005 : ¥18,980,000 (Direct Cost : ¥14,600,000、Indirect Cost : ¥4,380,000)
Fiscal Year 2004 : ¥18,980,000 (Direct Cost : ¥14,600,000、Indirect Cost : ¥4,380,000)
Fiscal Year 2003 : ¥18,980,000 (Direct Cost : ¥14,600,000、Indirect Cost : ¥4,380,000)
Fiscal Year 2002 : ¥35,620,000 (Direct Cost : ¥27,400,000、Indirect Cost : ¥8,220,000)
We isolated 42 out of 60 genomic DNA fragments that have been found by a large scale screening of aberrant DNA in hepatocellular carcinoma (HCC). These DNA showed hypermethylation in cancer. Thirty eight DNA are closely related to transcribed genes, among which eighteen are thought to be new methylated genes. RNA expression analysis of the 10 genes demonstrated cancer-specific suppression of expression. All eight genes tested have growth suppression activity by colony formation assay. Twenty three genes are classified in 4 signal transducers, 7 nuclear proteins including 4 transcription factors, 7 membrane proteins and 2 metabolic factors. We further analyzed functions of methylation-silenced genes in more detail. Three inhibitors of JAK/STAT pathway were inactivated in cancer which resulted in constitutive activation of STAT3, strongly suggesting significance of activated STAT3 in the development of HCC. We found that new machineries maintaining checkpoints were deregulated by methylation-silencing. A WNT family gene promoted cell growth in cooperation with FGF family proteins, while it acted as a tumor suppressor by inducing apoptosis when FGFs were not activated. This growth suppression was found to be independent of beta-catenin/TCF pathway, demonstrating that the WNT has a dual function. We also found a protein that interacted with DNA methyltransferase, was silenced by DNA methylation. Precise functional analysis of this gene is currently underway. These results indicate that aberrant methylation widely affects cancer genome and strongly suggest that methylation-silenced genes are critical for protecting genomic integrity and cancer.