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Journal of Cancer Research and Clinical Oncology

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01.05.2009 | Original Paper

Frequent inactivation of RUNX3 by promoter hypermethylation and protein mislocalization in oral squamous cell carcinomas

verfasst von: Feng Gao, Canhua Huang, Mei Lin, Zhi Wang, Jun Shen, Haiyuan Zhang, Lu Jiang, Qianming Chen

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 5/2009

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Abstract

Purpose

RUNX3 is a functionally important component in transforming growth factor-beta (TGF-β) mediated signaling pathway. Epigenetic silencing expression of RUNX3, as well as aberrant cytoplasmic retention of RUNX3 protein are causely involved in gastric carcinogenesis. Here, we examined the expression of RUNX3 gene and protein in oral squamous cell carcinomas (OSCCs) and analyzed the methylation status of RUNX3 promoter region.

Methods

About 10 normal oral mucosa and 30 OSCCs were collected to examine RUNX3 expression by RT-PCR analysis and immunohistochemistry assay using anti-RUNX3 monoclonal antibody R3-6E9. Methylation-specific PCR was carried out on the same specimens to analyze the methylation status of RUNX3 promoter. In addition, the stored paraffin-embedded specimens, including 40 oral leucoplakia (OLK) and 120 OSCCs, were examined by immunohistochemistry assay.

Results

RUNX3 gene and protein were underexpressed in OSCCs due to promoter hypermethylation. Protein mislocalization occured frequently. Both downregulation of RUNX3 protein expression (P = 0.001) and protein mislocalization (P = 0.001) were correlated with the differentiation grades in OSCCs.

Conclusions

RUNX3 plays an important role in oral carcinogenesis. It may be a useful diagnostic marker and a potential therapeutic target for OSCC.

Blobe GC, Schiemann WP, Lodish HF (2000) Role of transforming growth factor beta in human disease. N Engl J Med 342:1350–1358. doi:10.1056/NEJM200005043421807 PubMedCrossRef

Chim CS, Liang R, Tam CY, Kwong YL (2001) Methylation of p15 and p16 genes in acute promyelocytic leukemia: potential diagnostic and prognostic significance. J Clin Oncol 19:2033–2040PubMed

Goelz SE, Hamilton SR, Vogelstein B (1985) Purification of DNA from formaldehyde fixed and paraffin embedded human tissue. Biochem Biophys Res Commun 130:118–126. doi:10.1016/0006-291X(85)90390-0 PubMedCrossRef

Ha PK, Califano JA (2006) Promoter methylation and inactivation of tumour-suppressor genes in oral squamous-cell carcinoma. Lancet Oncol 7:77–82. doi:10.1016/S1470-2045(05)70540-4 PubMedCrossRef

Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93:9821–9826. doi:10.1073/pnas.93.18.9821 PubMedCrossRef

Hsu SM, Raine L, Fanger H (1981) Use of avidin-biotin-peroxidase complex (ABC) in immuno peroxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29:577–580PubMed

Ito K, Liu Q, Salto-Tellez M, Yano T, Tada K, Ida H et al (2005) RUNX3, a novel tumor suppressor, is frequently inactivated in gastric cancer by protein mislocalization. Cancer Res 65:7743–7750. doi:10.1158/0008-5472.CAN-05-0072 PubMedCrossRef

Ito Y, Miyazono K (2003) RUNX transcription factors as key targets of TGF-beta superfamily signaling. Curr Opin Genet Dev 13:43–47. doi:10.1016/S0959-437X(03)00007-8 PubMedCrossRef

Kim TY, Lee HJ, Hwang KS, Lee M, Kim JW, Bang YJ et al (2004) Methylation of RUNX3 in various types of human cancers and premalignant stages of gastric carcinoma. Lab Invest 84:479–484. doi:10.1038/labinvest.3700060 PubMedCrossRef

Kim WJ, Kim EJ, Jeong P, Quan C, Kim J, Li QL et al (2005) RUNX3 inactivation by point mutations and aberrant DNA methylation in bladder tumors. Cancer Res 65:9347–9354. doi:10.1158/0008-5472.CAN-05-1647 PubMedCrossRef

Kornberg LJ, Villaret D, Popp M, Lui L, McLaren R, Brown H et al (2005) Gene expression profiling in squamous cell carcinoma of the oral cavity shows abnormalities in several signaling pathways. Laryngoscope 115:690–698PubMed

Ku JL, Kang SB, Shin YK et al (2004) Promoter hypermethylation downregulates RUNX3 gene expression in colorectal cancer cell lines. Oncogene 23:6736–6742. doi:10.1038/sj.onc.1207731 PubMedCrossRef

Lau QC, Raja E, Salto-Tellez M, Liu Q, Lau QC, Ito K et al (2006) RUNX3 is frequently inactivated by dual mechanisms of protein mislocalization and promoter hypermethylation in breast cancer. Cancer Res 66:6512–6520. doi:10.1158/0008-5472.CAN-06-0369 PubMedCrossRef

Li QL, Ito K, Sakakura C, Fukamachi H, Inoue K, Chi XZ et al (2002) Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell 109:113–124. doi:10.1016/S0092-8674(02)00690-6 PubMedCrossRef

Li QL, Kim HR, Kim WJ, Choi JK, Lee YH, Kim HM et al (2004) Transcriptional silencing of RUNX3 gene by CpG hypermethylation is associated with lung cancer. Biochem Biophys Res Commun 314:223–228. doi:10.1016/j.bbrc.2003.12.079 PubMedCrossRef

Lund AH, Van LM (2002) RUNX: a trilogy of cancer genes. Cancer Cell 1:213–215. doi:10.1016/S1535-6108(02)00049-1 PubMedCrossRef

Ng HH, Bird A (1999) DNA methylation and chromatin modification. Curr Opin Genet Dev 9:158–163. doi:10.1016/S0959-437X(99)80024-0 PubMedCrossRef

Park WS, Cho YG, Kim CJ, Song JH, Lee YS, Kim SY et al (2005) Hypermethylation of the RUNX3 gene in hepatocellular Carcinoma. Exp Mol Med 37:276–281PubMed

Paterson IC, Matthews JB, Huntley S, Robinson CM, Fahey M, Parkinson EK, Prime EK (2001) Decreased expression of TGF-beta cell surface receptors during progression of human oral squamous cell carcinoma. J Pathol 193:458–467. doi:10.1002/1096-9896(2000)9999:9999<::AID-PATH822>3.0.CO;2-VPubMedCrossRef

Pindborg JJ, Reichart PA, Smith CJ (1997) Histological typing of cancer and precancer of the oral mucosa, 2nd edn. World Health Organization, Springer, Berlin

Rodrigues VC, Moss SM, Tuomainen H (1998) Oral cancer in the UK: to screen or not screen. Oral Oncol 34:454–465. doi:10.1016/S1368-8375(98)00052-9 PubMedCrossRef

Siegel P, Massague J (2003) Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer. Nat Rev Cancer 3:807–818. doi:10.1038/nrc1208 PubMedCrossRef

Taniuchi I, Osato M, Egawa T, Sunshine MJ, Bae SC, Komori T et al (2002) Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development. Cell 111:621–633. doi:10.1016/S0092-8674(02)01111-X PubMedCrossRef

Tanji Y, Osaki M, Nagahama Y, Kodani I, Ryoke K, Ito H (2007) Runt-related transcription factor 3 expression in human oral squamous cell carcinomas; implication for tumor progression and prognosis. Oral Oncol 43:88–94. doi:10.1016/j.oraloncology.2006.01.009 PubMedCrossRef

Torquati A, O’Rear L, Longobardi L, Spagnoli A, Richards WO, Daniel Beauchamp R (2004) RUNX3 inhibits cell proliferation and induces apoptosis by reinstating transforming growth factor beta responsiveness in esophageal adenocarcinoma cells. Surgery 136:310–316. doi:10.1016/j.surg.2004.05.005 PubMedCrossRef

Wada M, Yazumi S, Takaishi S, Hasegawa K, Sawada M, Tanaka H et al (2004) Frequent loss of RUNX3 gene expression in human bile duct and pancreatic cancer cell lines. Oncogene 23:2401–2407. doi:10.1038/sj.onc.1207395 PubMedCrossRef

Wei D, Gong W, Oh SC, Li Q, Kim WD, Wang L et al (2005) Loss of RUNX3 expression significantly affects the clinical outcome of gastric cancer patients and its restoration causes drastic suppression of tumor growth and metastasis. Cancer Res 65:4809–4816. doi:10.1158/0008-5472.CAN-04-3741 PubMedCrossRef

Woolf E, Xiao C, Fainaru O, Lotem J, Rosen D, Negreanu V et al (2003) Runx3 and Runx1 are required for CD8 T cell development during thymopoiesis. Proc Natl Acad Sci USA 100:7731–7736. doi:10.1073/pnas.1232420100 PubMedCrossRef

Xiao WH, Liu WW (2004) Hemizygous deletion and hypermethylation of RUNX3 gene in hepatocellular carcinoma. World J Gastroenterol 10:376–380PubMed

Titel: Frequent inactivation of RUNX3 by promoter hypermethylation and protein mislocalization in oral squamous cell carcinomas
verfasst von: Feng Gao
Canhua Huang
Mei Lin
Zhi Wang
Jun Shen
Haiyuan Zhang
Lu Jiang
Qianming Chen
Publikationsdatum: 01.05.2009
Verlag: Springer-Verlag
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 5/2009
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-008-0508-x

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Springer Medizin

Frequent inactivation of RUNX3 by promoter hypermethylation and protein mislocalization in oral squamous cell carcinomas

Abstract

Purpose

Methods

Results

Conclusions

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Abstract

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Conclusions

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