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01-10-2010 | Original Article

Loss of WW domain-containing oxidoreductase expression in the progression and development of gastric carcinoma: clinical and histopathologic correlations

Authors: Naoko Maeda, Shuho Semba, Shunji Nakayama, Kazuyoshi Yanagihara, Hiroshi Yokozaki

Published in: Virchows Archiv | Issue 4/2010

Abstract

The purpose of this study is to investigate the role of the WW domain-containing oxidoreductase (WWOX) tumor suppressor that maps to the common fragile site FRA16D (16q23.3-24.1) during the development of gastric carcinoma (GC), we examined the altered expression of WWOX in GC cell lines and tissue samples as well as the effects of restoration of the WWOX gene into WWOX-deficient GC cells. All GC cell lines (HSC-45, HSC-57, HSC-59, MKN-7, and MKN-74) showed reduced WWOX expression at the mRNA and protein levels and hypermethylation at the WWOX regulatory site was detected in HSC-45 and HSC-59 cells. Interestingly, treatment with the deacetylating agent trichostatin A and the demethylating agent 5-aza-2′-deoxycytidine restored endogenous WWOX expression levels in HSC-59 cells. Restoration of the WWOX gene with Ad-WWOX into HSC-59 cells effectively suppressed cell growth and increased the population of cells in subG₁ DNA content. In GC tissue samples, the loss of WWOX expression was detected in 24 (33%) of 73 GC cases in accordance with the hypermethylation at the WWOX regulatory site. Surprisingly, negative immunoreactivity against WWOX showed a significant relationship with several clinicopathologic findings, including histology (P = 0.0001), depth of invasion (P = 0.0004), lymph node metastasis (P = 0.0003), vessel infiltration (lymphatic vessels, P = 0.0167 and venous vessels, P = 0.0005), and clinicopathologic stage (P = 0.001). These findings suggest that repression of WWOX expression may play an important role in stomach carcinogenesis. WWOX thus appears to be a good biomarker for molecular diagnosis of the grade of malignancy of GCs.

Ohta M, Inoue H, Cotticelli MG et al (1996) The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnomal in digestive tract cancers. Cell 84:587–597CrossRefPubMed

Huebner K, Croce CM (2003) Cancer and the FRA3B/FHIT fragile locus: it's a HIT. Br J Cancer 88:1501–1506CrossRefPubMed

Bednarek AK, Laflin KJ, Daniel RL et al (2000) WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1, a region frequently affected in breast cancer. Cancer Res 60:2140–2145PubMed

Aqeilan RI, Palamarchuk A, Weigel RJ et al (2004) Physical and functional interactions between the Wwox tumor suppressor protein and the AP-2γ transcription factor. Cancer Res 101:4401–4406

Aqeilan RI, Donati V, Palamarchuk A et al (2005) WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function. Cancer Res 65:6764–6772CrossRefPubMed

Aqeilan RI, Pekarsky Y, Herrero JJ et al (2004) Functional association between Wwox tumor suppressor protein and p73, a p53 homolog. Proc Natl Acad Sci USA 101:4401–4406CrossRefPubMed

Chang NS, Doherty J, Ensign A et al (2005) WOX1 is essential for tumor necrosis factor-UV, light-, staurosporine-, and p53-mediated cell death, and its tyrosine 33-phospholrylated form binds and stabilizes serine 46-phosphorylated p53. J Biol Chem 280:43100–43108CrossRefPubMed

Paige AJ, Taylor KJ, Taylor C et al (2001) WWOX: a candidate tumor suppressor gene involved in multiple tumor types. Proc Natl Acad Sci USA 98:11417–11422CrossRefPubMed

Driouch K, Prydz H, Monese R et al (2002) Alternative transcripts of the candidate tumor suppressor gene, WWOX, are expressed at high levels in human breast tumors. Oncogene 21:1832–1840CrossRefPubMed

10.

Kuroki T, Trapasso F, Shiraishi T et al (2002) Genetic alterations of the tumor suppressor gene WWOX in esophageal squamous cell carcinoma. Cancer Res 62:2258–2260PubMed

11.

Yendamuri S, Kuroki T, Trapasso F et al (2003) WW domain containing oxidoreductase gene expression is altered in non-small cell lung cancer. Cancer Res 63:878–881PubMed

12.

Kuroki T, Yendamuri S, Trapasso F et al (2004) The tumor suppressor gene WWOX at FRA16D is involved in pancreatic carcinogenesis. Clin Cancer Res 10:2459–2465CrossRefPubMed

13.

Nakayama S, Semba S, Maeda N et al (2008) Role of the WWOX gene, encompassing fragile region FRA16D, in suppression of pancreatic carcinoma cells. Cancer Sci 99:1370–1376CrossRefPubMed

14.

Fabbri M, Iliopoulos D, Trapasso F et al (2005) WWOX gene restration prevents lung cancer growth in vitro and in vivo. Proc Natl Acad Sci USA 102:15611–15616CrossRefPubMed

15.

Qin HR, Iliopoulos D, Semba S et al (2006) A role for the WWOX gene in prostete cancer. Cancer Res 66:6477–6481CrossRefPubMed

16.

Aqeilan RI, Kuroki T, Pekarsky Y et al (2004) Loss of WWOX expression in gastric carcinoma. Clin Cancer Res 10:3053–3058CrossRefPubMed

17.

Yanagihara K, Ito A, Toge T et al (1993) Antiproliferative effects of isoflavones on human cancer cell lines established from the gastrointestinal tract. Cancer Res 53:5815–5821PubMed

18.

Yanagihara K, Seyama T, Tsumuraya M et al (1991) Establishment and characterization of human signet ring cell gastric carcinoma cell lines with amplification of the c-myc oncogene. Cancer Res 51:381–386PubMed

19.

Hojo H (1977) Establishment of cultured cell lines of human stomach cancer—origin and their morphological characteristics. (in Japanese) Niigata Igakukai Zassi 91:737–752

20.

Motoyama T, Hojo H, Watanabe H (1986) Comparison of seven cell lines derived from human gastric carcinomas. Acta Pathol Jpn 36:65–83PubMed

21.

Japanse Gastric Cancer Association (2010) Japanese classification of gastric carcinoma, 14th edn. Kanehara Ltd, Tokyo

22.

Watanabe A, Hippo Y, Taniguchi H et al (2003) An opposing view on WWOX protein function as a tumor suppressor. Cancer Res 63:8629–8633PubMed

23.

Iliopoulos D, Guler G, Han SY et al (2005) Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer. Oncogene 24:1625–1633CrossRefPubMed

24.

Nakayama S, Semba S, Maeda N et al (2009) Hypermethyaltion-mediated reduction of WWOX expression in intraductal papillary mucinous neoplasms of the pancreas. Br J Cancer 100:1438–1443CrossRefPubMed

25.

Mahajan NP, Whang TE, Mohler JL et al (2005) Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox. Cancer Res 65:10514–10523CrossRefPubMed

26.

Lai FJ, Cheng CL, Chen ST et al (2005) WOX1 is essential for UVB irradiation-induced apoptosis and down-regulated via translational blockade in UVB-induced cutaneous squamous cell carcinoma in vivo. Clin Cancer Res 11:5769–5777CrossRefPubMed

27.

Gourley C, Paige AJW, Taylor KJ et al (2009) WWOX gene expression abolishes ovarian cancer tumorigenicity in vivo and decreases attachment to fibronectin via Integrin α₃. Cancer Res 69:4835–4842CrossRefPubMed

28.

Aqeilan RI, Trapasso F, Hussain S et al (2007) Targeted deletion of Wwox reveals a tumor suppressor function. Proc Natl Acad Sci USA 104:3949–3954CrossRefPubMed

29.

Aqeilan RI, Hagan JP, Aqeilan HA et al (2007) Inactivation of the Wwox gene accelerates forestomach tumor progression in vivo. Cancer Res 67:5606–5610CrossRefPubMed

Title: Loss of WW domain-containing oxidoreductase expression in the progression and development of gastric carcinoma: clinical and histopathologic correlations
Authors: Naoko Maeda
Shuho Semba
Shunji Nakayama
Kazuyoshi Yanagihara
Hiroshi Yokozaki
Publication date: 01-10-2010
Publisher: Springer-Verlag
Published in: Virchows Archiv / Issue 4/2010
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-010-0956-y

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Loss of WW domain-containing oxidoreductase expression in the progression and development of gastric carcinoma: clinical and histopathologic correlations

Abstract

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Abstract

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