Hypermethylation of the RUNX3 gene in hepatocellular carcinoma

다국어 초록 (Multilingual Abstract)

Methylation events play a critical role in various cellular processes including regulation of gene transcription and proliferation. Recently, RUNX3 β-Smads signaling transduction pathway genes, showed strong tumor-suppressor activity by regulation of epithelial proliferation and apoptosis. To elucidate the potential etiological role of the RUNX3 gene in the development of hepato-cellular carcinoma (HCC), we have analyzed the methylation status of 5' CpG island of the RUNX3 gene in a series of 73 HCC tissues and 1 liver cell lines. Expectedly, promoter methylation of RUNX3 gene was found in 2 (2.7%) of 73 corresponding normal liver, whereas 30 (41.1%) of 73 HCCs and 4 (40%) of 10 liver cancer cell lines showed hypermethylation of the gene, respectively. There was no significant difference between promoter hypermethylaion and clinicopathologic parameters of primary HCC sam-ples, including histologic grade, microvascular invasion, and clinical stage. Interestingly, demethy-lating agent 5-aza-2-deoxycytidine induced reacti-vation and more potent expression of RUNX3 gene in HCC cell lines. Our findings indicate that promoter hypermethylation of RUNX3 gene may occur as an early event in the development of HCC and that methylation may be a major mechanism for inactivation of RUNX3 gene in HCC.

참고문헌 (Reference)

1 "systematic investigation of critical experimentalparameters. Nucleic Acids Res 2001" 29 : e65-5,

2 "andSmad4 in hepatocellular carcinoma. Int J Oncol 1999" 14 : 127-31,

3 "Vogelstein B. Purification of DNAfrom formaldehyde fixed and paraffin embedded humantissue. Biochem Biophys Res Commun 1985" 130 : 118-26,

4 "Vance J. Report of thesecond international workshop on human chromosome 1mapping 1995. Cytogenet Cell Genet 1996" 72 : 114-44,

5 "Transforming growth factor beta1 inhibits mouse keratinocytes late in G1 independent ofeffects on gene transcription. Cancer Res 1995" 1452-7,

6 "The transforming growth factor-beta signalingpathway in tumorigenesis. Curr Opin Oncol 2001" 70-7,

7 "Park JG. Promoter hypermethylation downregulatesRUNX3 gene expression in colorectal cancer celllines. Oncogene 2004" 6736-42,

8 "Park JG. 139 KCCR-affiliatedHospitals. 2002 annual report of the Korea central cancerregistry Based on registered data from 139 hospitals.Cancer Research and Treatment 2004" 36 : 103-14, 2004

9 "Miyaki M. Suppression of tumourigenicity in humancolon carcinoma cells by introduction of normal chromosome1p36 region. Oncogene 1993" 8 (8): 2253-8,

10 "Liu W-W. Hemizygous deletion and hypermethylationof RUNX3 gene in hepatocellular carcinoma.World J Gastroenterol 2004" 10 : 376-80,

11 "LianJB. Integration of Runx and Smad regulatory signals attranscriptionally active subnuclear sites. Proc Natl Acad SciUSA 2002" 99 : 8048-53,

12 "Kreipe H. Quantitativeanalysis of promoter hypermethylation in laser-microdissectedarchival specimens. Lab Invest 2001" 635-7,

13 "Kern SE.DPC4 gene in various tumor types. Cancer Res 1996" Weinstein CL 2527-30,

14 "KangGH. Methylation of RUNX3 in various types of humancancers and premalignant stages of gastric carcinoma. LabInvest 2004" 84 : 479-84,

15 "Kang GH.Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis.Am J Pathol 2003" 1371-78,

16 "Ito Y. Causal relationshipbetween the loss of RUNX3 expression and gastriccancer. Cell 2002" ya (ya): 113-24,

17 "Issa JP. CpG island methylator phenotypes in aging and cancer" Issa JP. CpG island methylator phenotypes inaging and cancer. Semin Cancer Biol 1999 9 : 349-57,

18 "Issa JP. CpG island methylator phenotype in colorectal cancer.Proc Natl Acad Sci USA 1999" 8681-6, 1999

19 "Hong SD. Inactivation patterns ofp16/INK4A in oral squamous cell carcinomas. Exp Mol Med2004" 165-71,

20 "Heldin C. Mechanisms ofTGF-beta signaling in regulation of cell growth anddifferentiation. Immunol Lett 2002" 85-91,

21 "Hagiwara K. Mutational analysis of the Smad6and Smad7 genes in hepatocellular carcinoma. Int J MolMed 2001" take (take): 49-52,

22 "Derynck R. Transcriptional regulation of the transforminggrowth factor-beta-inducible mouse germ line Igalpha constant region gene by functional corporation ofSmad" 16979-85,

23 "Chronic liver injury^TGF-β^cancer. Exp MolMed" 33 : 179-90, 2001

24 "Choi JK. Tumor suppressor activity of RUNX3. Oncogene2004" 4336-40,

25 "Chiba T. Frequentloss of RUNX3 gene expression in human bile duct andpancreatic cancer cell lines. Oncogene 2004" 2401-7,