Journal List > Korean J Urol > v.50(5) > 1005325

TOOLS
Kwon, Park, Kim, Ha, Kim, Yun, Lee, and Kim: The Relationship between RUNX3 Inactivation and Its Pathological Features in Renal Cell Carcinoma
Original Article
Urological Oncology
Korean Journal of Urology

Korean Journal of Urology 2009; 50(5): 432-438.

Published online: 25 May 2009

DOI: https://doi.org/10.4111/kju.2009.50.5.432

The Relationship between RUNX3 Inactivation and Its Pathological Features in Renal Cell Carcinoma

Whi-An Kwon, Cheol Park, Eun-Jung Kim, Yun-Sok Ha, Yong-June Kim, Seok-Joong Yun, Sang-Cheol Lee, Wun-Jae Kim

Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Korea.

Correspondence to: Yong-June Kim. Department of Urology, College of Medicine, Chungbuk National University, 62, Gaesin-dong, Heungdeok-gu, Cheongju 361-711, Korea. TEL: 043-269-6134, FAX: 043-269-6143, urokyj@cbnu.ac.kr

Received 11 March 2009       Accepted 30 March 2009

Copyright © The Korean Urological Association, 2009

Abstract

Purpose

DNA methylation is a key regulator of gene transcription and genomic stability, and alterations in DNA methylation are frequently detected in human tumors. Recent study has suggested that inactivation of runt-related transcription factor 3 (RUNX3), primarily epigenetic alterations in DNA methylation, is closely associated with bladder tumor stage, grade, and prognosis. The aim of this study was to evaluate the association between RUNX3 inactivation and renal cell carcinoma (RCC).

Materials and Methods

RCC tissues (n=56) were obtained from patients who underwent radical nephrectomy. The methylation pattern of RUNX3 was determined by using methylation specific-polymerase chain reaction (MS-PCR) and direct DNA sequencing.

Results

Methylation of the RUNX3 promoter was observed in 75.0% of the samples (42/56). The tumor stage and grade were significantly associated with the methylation status (p<0.05, respectively). However, recurrence and progression of RCC were not significantly related to the methylation of the RUNX3 promoter region (log-rank test, p>0.05, respectively).

Conclusions

This study demonstrated that promoter methylation of RUNX3 is frequently observed in RCC. In addition, RUNX3 methylation is closely associated with aggressive pathologic features.

Keywords: Human RUNX3 protein, Methylation, Renal cell carcinoma

Figures and Tables

Fig. 1
Nucleotide sequence of runt-related transcription factor 3 (RUNX3) promoter region. Nucleotide sequence from -880 to +1 region is shown. CpG dinucleotides are marked in bold.
kju-50-432-g001
Fig. 2
Methylation of the runt-related transcription factor 3 (RUNX3) promoter region in renal cell carcinoma (RCC) cell lines. DNA from 5 RCC cell lines was analyzed by methylation specific polymerase chain reaction (PCR) followed by direct DNA sequencing. Methylated CpG cytosines remained as cytosines, whereas unmethylated cytosines changed to thymidines in the PCR products.
kju-50-432-g002
Table 1
Patients and pathologic classification
kju-50-432-i001
Table 2
Correlation of RUNX3 methylation statuswith age, sex, histology, recurrence and progression
kju-50-432-i002

RUNX3: runt-related transcription factor 3, a: Fisher's exact test, b: chi-square test

Table 3
Correlation of RUNX3 methylation status with stage and grade
kju-50-432-i003

RUNX3: runt-related transcription factor 3, a: chi-square, linear by linear association

Notes

This work was supported by the research grant of the Chungbuk National University in 2008.

References

1. Linehan WM, Zbar B, Bates SE, Zelefsky MJ, Yang JC. Devita VT, Hellman S, Rosenberg SA, editors. Cancer of the kidney and ureter. Cancer: principles and practice of oncology. 2001. 6th ed. Philadelphia: Lippincott;1362–1395.
2. Ficarra V, Righetti R, Pilloni S, D'amico A, Maffei N, Novella G, et al. Prognostic factors in patients with renal cell carcinoma: retrospective analysis of 675 cases. Eur Urol. 2002. 41:190–198.
3. Pavlovich CP, Schmidt LS, Phillips JL. The genetic basis of renal cell carcinoma. Urol Clin North Am. 2003. 30:437–454.
4. Wong IH, Lo YM, Zhang J, Liew CT, Ng MH, Wong N, et al. Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients. Cancer Res. 1999. 59:71–73.
5. Ohtani-Fujita N, Dryja TP, Rapaport JM, Fujita T, Matsumura S, Ozasa K, et al. Hypermethylation in the retinoblastoma gene is associated with unilateral, sporadic retinoblastoma. Cancer Genet Cytogenet. 1997. 98:43–49.
6. Horikawa Y, Sugano K, Shigyo M, Yamamoto HO, Nakazono M, Fujimoto H, et al. Hypermethylation of an E-cadherin (CDH1) promoter region in high grade transitional cell carcinoma of the bladder comprising carcinoma in situ. J Urol. 2003. 169:1541–1545.
7. Kim EJ, Kim WJ. The causal relationship between RUNX3 and bladder tumor. Korean J Urol. 2005. 46:1192–1198.
8. Yates DR, Rehman I, Abbod MF, Meuth M, Cross SS, Linkens DA, et al. Promoter hypermethylation identifies progression risk in bladder cancer. Clin Cancer Res. 2007. 13:2046–2053.
9. Lund AH, van Lohuizen M. RUNX: a trilogy of cancer genes. Cancer Cell. 2002. 1:213–215.
10. Li QL, Ito K, Sakakura C, Fukamachi H, Inoue K, Chi XZ, et al. Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell. 2002. 109:113–124.
11. Bae SC, Lee YH. Phosphorylation, acetylation and ubiquitination: the molecular basis of RUNX regulation. Gene. 2006. 366:58–66.
12. Kim WJ, Kim EJ, Jeong P, Quan C, Kim J, Li QL, et al. RUNX3 inactivation by point mutations and aberrant DNA methylation in bladder tumors. Cancer Res. 2005. 65:9347–9354.
13. Li QL, Kim HR, Kim WJ, Choi JK, Lee YH, Kim HM, et al. Transcriptional silencing of the RUNX3 gene by CpG hypermethylation is associated with lung cancer. Biochem Biophys Res Commun. 2004. 314:223–228.
14. Wada M, Yazumi S, Takaishi S, Hasegawa K, Sawada M, Tanaka H, et al. Frequent loss of RUNX3 gene expression in human bile duct and pancreatic cancer cell lines. Oncogene. 2004. 23:2401–2407.
15. Xiao WH, Liu WW. Hemizygous deletion and hypermethylation of RUNX3 gene in hepatocellular carcinoma. World J Gastroenterol. 2004. 10:376–380.
16. Green FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller DG, et al. . AJCC cancer staging manual. 2002. 6th ed. New York: Springer-Verlag;323–328.
17. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982. 6:655–663.
18. Frommer M, McDonald LE, Millar DS, Collis CM, Watt F, Grigg GW, et al. A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci USA. 1992. 89:1827–1831.
19. Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, et al. Mutations in the p53 gene occur in diverse human tumour types. Nature. 1989. 342:705–708.
20. Nuovo GJ, Plaia TW, Belinsky SA, Baylin SB, Herman JG. In situ detection of the hypermethylation-induced inactivation of the p16 gene as an early event in oncogenesis. Proc Natl Acad Sci USA. 1999. 96:12754–12759.
21. Catto JW, Azzouzi AR, Rehman I, Feeley KM, Cross SS, Amira N, et al. Promoter hypermethylation is associated with tumor location, stage, and subsequent progression in transitional cell carcinoma. J Clin Oncol. 2005. 23:2903–2910.
22. Goel A, Arnold CN, Tassone P, Chang DK, Niedzwiecki D, Dowell JM, et al. Epigenetic inactivation of RUNX3 in microsatellite unstable sporadic colon cancers. Int J Cancer. 2004. 112:754–759.
23. Kim EJ, Kim YJ, Jeong P, Ha YS, Bae SC, Kim WJ. Methylation of the RUNX3 promoter as a potential prognostic marker for bladder tumor. J Urol. 2008. 180:1141–1145.
24. Rini BI, Rathmell WK. Biological aspects and binding strategies of vascular endothelial growth factor in renal cell carcinoma. Clin Cancer Res. 2007. 13:741s–746s.
25. Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006. 295:2516–2524.
26. Won YY, Joo HJ, Cho DS, Seo KS, Ahn BC, Kim KH, et al. Correlation of caveolin-1 expression on tissue microarray with prognosis in renal cell carcinoma. Korean J Urol. 2006. 47:607–613.
27. Cho YH, Jang TJ, Lee KS. Expression of cyclooxygenase-2 and microsomal prostaglandin E2 synthase-1 in human renal cell carcinoma. Korean J Urol. 2005. 46:1057–1063.
28. Kwon NS, Jo MK, Lee HM. Serum levels of vascular endothelial growth factor (VEGF) as a prognostic factor in renal cell carcinoma. Korean J Urol. 2007. 48:1219–1223.
29. Oh BS, Park SH, Park YI. Significance of thrombocytosis as a prognostic factor after radical nephrectomy in patients with renal cell carcinoma. Korean J Urol. 2004. 45:1095–1099.
30. Kim YK, Kim SI, Kim SJ. Significance of erythrocyte sedimentation rate and C-reactive protein as predictive factors for prognosis in non-metastatic renal cell carcinoma. Korean J Urol. 2006. 47:1059–1064.
TOOLS
Similar articles