Abstract
Background: Our previous studies suggested that deficient function of RUNX3 protein is causally related to development and progression of human gastric cancer. RUNX3 is mapped to 1p36, which is frequently deleted in hepatocellular carcinomas (HCC), therefore, these tumors were investigated for expression and copy number changes of RUNX3 and other Runt-related genes, RUNX1, RUNX2, and their co-factor CBFβ. Similarly nearby uninvolved liver showing cirrhosis or normal histology was investigated in conjunction with various clinicopathological factors. Materials and Methods: Copy number change and expression change of RUNX family genes in 35 hepatocellular carcinoma specimens and adjoining liver with cirrhosis (LC) or normal histology were estimated using quantitative reverse transcription polymerase chain reaction (RT-PCR) and in situ hybridization. Results: Among RUNX family genes, only RUNX3 showed frequent hemizygous deletion in HCC (40%, 17 out of 35 cases). Ratios of RUNX mRNA to β-actin mRNA (x103) for RUNX1 were 21.7±9.1, 11.8±5.6 and 5.5±2.5; for RUNX2, 0.7±0.7, 0.5±0.4 and 0.4±0.1; for RUNX3, 23.3±7.6, 5.8±2.3 and 1.9±0.9; for CBFβ, 17.9±7.0, 8.9±3.1 and 5.5±2.1 (normal vs. LC vs. tumor, respectively, mean±SD). Basal RUNX2 expression was very weak, with no significant difference between HCC and other groups. In contrast, RUNX1 and RUNX3 showed remarkable down-regulation in 75% and 92% of HCC, respectively, as well as in 55% and 71% of specimens with LC, a precancerous lesion for HCC. Furthermore, CBFβ, an important cofactor of RUNX1, -2 and -3, also was significantly downregulated, but less frequently and intensely than either RUNX1 or RUNX3. Prevalence of downregulation of RUNX1, RUNX3 and CBFβ increased as LC progressed to HCC and as cancer stage progressed, suggesting that RUNX family genes may be involved early in hepatocarcinogenesis, as well as in cancer progression. Conclusion: These findings suggest that RUNX3, as well as RUNX1 and CBFβ play important roles in hepato-carcinogenesis and that RUNX gene family involvement in hepatocarcinogenesis may be more widespread and complex than previously realized.
Footnotes
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Abbreviations: CBF, core binding factor; PEBP2, polyomavirus enhancer binding protein 2; FISH, fluorescence in situ hybridization; RT-PCR, reverse transcriptase-polymerase chain reaction; MSP, methylation-specific polymerase chain reaction; HCC, hepatocellular carcinoma; LC, liver cirrhosis; PBS, phosphate-buffered saline.
- Received May 29, 2006.
- Accepted July 13, 2006.
- Copyright© 2006 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved