Decreased expression and frequent allelic inactivation of the RUNX3 gene at 1p36 in human hepatocellular carcinoma.
OBJECTIVE
Alteration in transforming growth factor-beta signaling pathway is one of the main causes of hepatocellular carcinoma (HCC). The human runt-related transcription factor 3 gene (RUNX3) is an important component of this pathway. RUNX3 locus 1p36 is commonly deleted in a variety of human cancers, including HCC. Therefore, we examined genetic and epigenetic alterations of RUNX3 in human HCC.


METHODS
Five HCC cell lines and 41 patients with HCC were investigated in this study. We examined the expression of RUNX3 mRNA, methylation status of RUNX3 promoter region, loss of heterozygosity (LOH) at 1p36, and mutation analysis. These results were compared with clinicopathological data.


RESULTS
Promoter hypermethylation was detected in four (80%) of five HCC cell lines and 31 (75.6%) of 41 HCC tissues, confirmed by sequence of bisulfite-treated DNA. LOH was detected in 14 (37.8%) of 37 HCC. By comparison with clinicopathological data, hypermethylation was more common in hepatitis C virus antibody and formation of capsule-positive cases, and decrease of expression was correlated strongly with advanced stage and LOH-detected cases.


CONCLUSIONS
Hypermethylation and LOH appear to be common mechanisms for inactivation of RUNX3 in HCC. Therefore, RUNX3 may be an important tumor suppressor gene related to hepatocarcinogenesis.
Mori
Toshiaki
T
Department of Surgery II, Graduate School & Faculty of Medicine, University of Nagoya, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Nomoto
Shuji
S
Koshikawa
Katsumi
K
Fujii
Tsutomu
T
Sakai
Mitsuru
M
Nishikawa
Yoko
Y
Inoue
Soichiro
S
Takeda
Shin
S
Kaneko
Tetsuya
T
Nakao
Akimasa
A
D000483:Alleles; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D050677:Core Binding Factor Alpha 3 Subunit; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000032:analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation; D011336:Probability; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D014157:Transcription Factors / Q000235:genetics*
D050677:Core Binding Factor Alpha 3 Subunit; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C493729:Runx3 protein, human; D014157:Transcription Factors