Regulation of RUNX3 Tumor Suppressor Gene Expression in Cutaneous Melanoma

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2009 Apr 2

PMID 19336521

Citations 52

Authors

Minoru Kitago

Steve R Martinez

Takeshi Nakamura

Myung-Shin Sim

Dave S B Hoon

Affiliations

Soon will be listed here.

Abstract

Purpose: RUNX3 is a known tumor suppressor gene in several carcinomas. Aberration in RUNX3 expression has not been described for cutaneous melanoma. Therefore, we assessed the expression of RUNX3 in cutaneous melanoma and its regulatory mechanisms relative to tumor progression.

Experimental Design: The expression of RUNX3 mRNA and miR-532-5p (microRNA) was assessed in melanoma lines and in primary and metastatic melanoma tumors.

Results: RUNX3 mRNA expression was down-regulated in 11 of 11 (100%) metastatic melanoma lines relative to normal melanocytes (P < 0.001). Among 123 primary and metastatic melanoma tumors and 12 normal skin samples, RUNX3 expression was significantly down-regulated in primary melanomas (n = 82; P = 0.02) and in melanoma metastasis (n = 41; P < 0.0001) versus normal skin (n = 12). This suggested that RUNX3 down-regulation may play a role in the development and progression of melanoma. RUNX3 promoter region hypermethylation was assessed as a possible regulator of RUNX3 expression using methylation-specific PCR. Assessment of RUNX3 promoter region methylation showed that only 5 of 17 (29%) melanoma lines, 2 of 52 (4%) primary melanomas, and 5 of 30 (17%) metastatic melanomas had hypermethylation of the promoter region. A microRNA (miR-532-5p) was identified as a target of RUNX3 mRNA sequences. miR-532-5p expression was shown to be significantly up-regulated in melanoma lines and metastatic melanoma tumors relative to normal melanocytes and primary melanomas, respectively. To investigate the relation between RUNX3 and miR-532-5p, anti-miR-532-5p was transfected into melanoma lines. Inhibition of miR-532-5p up-regulated both RUNX3 mRNA and protein expression.

Conclusions: RUNX3 is down-regulated during melanoma progression and miR-532-5p is a regulatory factor of RUNX3 expression.

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References

Mueller W, Nutt C, Ehrich M, Riemenschneider M, Deimling A, van den Boom D . Downregulation of RUNX3 and TES by hypermethylation in glioblastoma. Oncogene. 2006; 26(4):583-93. DOI: 10.1038/sj.onc.1209805. View

Ito Y . Oncogenic potential of the RUNX gene family: 'overview'. Oncogene. 2004; 23(24):4198-208. DOI: 10.1038/sj.onc.1207755. View

Kim T, Lee H, Hwang K, Lee M, Kim J, Bang Y . Methylation of RUNX3 in various types of human cancers and premalignant stages of gastric carcinoma. Lab Invest. 2004; 84(4):479-84. DOI: 10.1038/labinvest.3700060. View

Hoon D, Spugnardi M, Kuo C, Huang S, Morton D, Taback B . Profiling epigenetic inactivation of tumor suppressor genes in tumors and plasma from cutaneous melanoma patients. Oncogene. 2004; 23(22):4014-22. PMC: 2856469. DOI: 10.1038/sj.onc.1207505. View

Koyanagi K, ODay S, Gonzalez R, Lewis K, Robinson W, Amatruda T . Serial monitoring of circulating melanoma cells during neoadjuvant biochemotherapy for stage III melanoma: outcome prediction in a multicenter trial. J Clin Oncol. 2005; 23(31):8057-64. PMC: 2856446. DOI: 10.1200/JCO.2005.02.0958. View

Nakamura S, Senzaki K, Yoshikawa M, Nishimura M, Inoue K, Ito Y . Dynamic regulation of the expression of neurotrophin receptors by Runx3. Development. 2008; 135(9):1703-11. DOI: 10.1242/dev.015248. View

Umetani N, de Maat M, Mori T, Takeuchi H, Hoon D . Synthesis of universal unmethylated control DNA by nested whole genome amplification with phi29 DNA polymerase. Biochem Biophys Res Commun. 2005; 329(1):219-23. DOI: 10.1016/j.bbrc.2005.01.088. View

He L, Hannon G . MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004; 5(7):522-31. DOI: 10.1038/nrg1379. View

Ito K, Lim A, Salto-Tellez M, Motoda L, Osato M, Chuang L . RUNX3 attenuates beta-catenin/T cell factors in intestinal tumorigenesis. Cancer Cell. 2008; 14(3):226-37. DOI: 10.1016/j.ccr.2008.08.004. View

10.

Calin G, Croce C . MicroRNA signatures in human cancers. Nat Rev Cancer. 2006; 6(11):857-66. DOI: 10.1038/nrc1997. View

11.

Hiramatsu T, Osaki M, Ito Y, Tanji Y, Tokuyasu N, Ito H . Expression of RUNX3 protein in human esophageal mucosa and squamous cell carcinoma. Pathobiology. 2006; 72(6):316-24. DOI: 10.1159/000091329. View

12.

Sempere L, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V . Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol. 2004; 5(3):R13. PMC: 395763. DOI: 10.1186/gb-2004-5-3-r13. View

13.

Hussein M, Roggero E, Tuthill R, Wood G, Sudilovsky O . Identification of novel deletion Loci at 1p36 and 9p22-21 in melanocytic dysplastic nevi and cutaneous malignant melanomas. Arch Dermatol. 2003; 139(6):816-7. DOI: 10.1001/archderm.139.6.816. View

14.

Inoue K, Shiga T, Ito Y . Runx transcription factors in neuronal development. Neural Dev. 2008; 3:20. PMC: 2531103. DOI: 10.1186/1749-8104-3-20. View

15.

Araki K, Osaki M, Nagahama Y, Hiramatsu T, Nakamura H, Ohgi S . Expression of RUNX3 protein in human lung adenocarcinoma: implications for tumor progression and prognosis. Cancer Sci. 2005; 96(4):227-31. PMC: 11158107. DOI: 10.1111/j.1349-7006.2005.00033.x. View

16.

Umetani N, Takeuchi H, Fujimoto A, Shinozaki M, Bilchik A, Hoon D . Epigenetic inactivation of ID4 in colorectal carcinomas correlates with poor differentiation and unfavorable prognosis. Clin Cancer Res. 2004; 10(22):7475-83. DOI: 10.1158/1078-0432.CCR-04-0689. View

17.

Zhang B, Pan X, Cobb G, Anderson T . microRNAs as oncogenes and tumor suppressors. Dev Biol. 2006; 302(1):1-12. DOI: 10.1016/j.ydbio.2006.08.028. View

18.

Li Q, Ito K, Sakakura C, Fukamachi H, Inoue K, Chi X . Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell. 2002; 109(1):113-24. DOI: 10.1016/s0092-8674(02)00690-6. View

19.

Balch C, Soong S, Atkins M, Buzaid A, Cascinelli N, Coit D . An evidence-based staging system for cutaneous melanoma. CA Cancer J Clin. 2004; 54(3):131-49. DOI: 10.3322/canjclin.54.3.131. View

20.

Tang F, Hajkova P, Barton S, Lao K, Surani M . MicroRNA expression profiling of single whole embryonic stem cells. Nucleic Acids Res. 2006; 34(2):e9. PMC: 1351374. DOI: 10.1093/nar/gnj009. View