Intratumoral Wnt2B expression affects tumor proliferation and survival in malignant pleural mesothelioma patients

Kobayashi,Masashi; Huang,Cheng-Long; Sonobe,Makoto; Kikuchi,Ryutaro; Ishikawa,Masashi; Kitamura,Jiro; Miyahara,Ryo; Menju,Toshi; Iwakiri,Shotaro; Itoi,Kazumi; Yasumizu,Ryoji; Date,Hiroshi

doi:10.3892/etm.2012.511

Intratumoral Wnt2B expression affects tumor proliferation and survival in malignant pleural mesothelioma patients

Authors:
- Masashi Kobayashi
- Cheng-Long Huang
- Makoto Sonobe
- Ryutaro Kikuchi
- Masashi Ishikawa
- Jiro Kitamura
- Ryo Miyahara
- Toshi Menju
- Shotaro Iwakiri
- Kazumi Itoi
- Ryoji Yasumizu
- Hiroshi Date
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Affiliations: Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan, Department of Thoracic Surgery, Hyogo Prefectural Amagasaki Hospital, Amagasaki, Japan, Department of Pathology, Hyogo Prefectural Tsukaguchi Hospital, Amagasaki, Japan
Published online on: March 12, 2012 https://doi.org/10.3892/etm.2012.511
Pages: 952-958

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Abstract

Malignant pleural mesothelioma (MPM) is an aggressive thoracic tumor with a poor prognosis. We performed a comprehensive clinical study on the intratumoral expression of Wnt1, Wnt2B and Wnt5A in MPM. One hundred and seven MPM patients were investigated. Immunohistochemistry was performed to evaluate the intratumoral expression of Wnt1, Wnt2B, Wnt5A, survivin and c-Myc, and the Ki-67 proliferation index. The apoptotic index was evaluated by the TUNEL method. Among the 107 MPMs, 23 MPMs (21.5%) were Wnt1-high tumors, 72 MPMs (67.3%) were Wnt2B-high tumors and 54 MPMs (50.5%) were Wnt5A-high tumors. There was no correlation among the levels of Wnt expression. The percentage of Wnt2B-positive tumors was significantly higher compared to that of the other Wnts (p<0.0001). Furthermore, intratumoral Wnt2B expression significantly correlated with the expression of survivin (p<0.001) and c-Myc (p<0.001). Regarding tumor biology, the Ki-67 proliferation index was significantly higher in the Wnt2B-high tumors than in the Wnt2B-low tumors (p=0.0438). In addition, the overall survival was significantly lower in patients with Wnt2B-high tumors than in those with Wnt2B-low tumors (p=0.0238). A Cox multivariate analysis also demonstrated the Wnt2B status to be a significant prognostic factor in MPM patients (p=0.0042). Intratumoral Wnt2B expression was associated with the expression of survivin and c-Myc, tumor proliferation and patient survival in MPM. Wnt2B is a potential molecular target for the treatment of Wnt2B-overexpressing MPMs.

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1.	Greillier L and Astoul P: Mesothelioma and asbestos-related pleural diseases. Respiration. 76:1–15. 2008. View Article : Google Scholar : PubMed/NCBI
2.	Bueno R: Mesothelioma clinical presentation. Chest. 116(Suppl 6): S444–S445. 1999. View Article : Google Scholar
3.	Fujimoto N, Aoe K, Gamba K, Kato K, Yamazaki K and Kishimoto T: Clinical investigation of malignant mesothelioma in Japan. J Cancer Res Clin Oncol. 136:1755–1759. 2010. View Article : Google Scholar : PubMed/NCBI
4.	Schil PE, Bass P, Gaafar R, et al: Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial. Eur Respir J. 36:1362–1369. 2010. View Article : Google Scholar : PubMed/NCBI
5.	Dale TC: Signal transduction by the Wnt family of ligands. Biochem J. 329:209–223. 1998.
6.	You Z, Saims D, Chen S, et al: Wnt signaling promotes oncogenic transformation by inhibiting c-Myc-induced apoptosis. J Cell Biol. 157:429–440. 2002. View Article : Google Scholar : PubMed/NCBI
7.	Huang C, Liu D, Masuya D, et al: MRP-1/CD9 gene transduction downregulates Wnt signal pathways. Oncogene. 23:7475–7483. 2004. View Article : Google Scholar : PubMed/NCBI
8.	Huang C, Liu D, Ishikawa S, et al: Wnt1 overexpression promotes tumour progression in non-small cell lung cancer. Eur J Cancer. 44:2680–2688. 2008. View Article : Google Scholar : PubMed/NCBI
9.	Huang C, Liu D, Nakano J, et al: Wnt5a expression is associated with the tumor proliferation and the stromal vascular endothelial growth factor-A expression in non-small cell lung cancer. J Clin Oncol. 23:8765–8773. 2005. View Article : Google Scholar : PubMed/NCBI
10.	Chen G, Shukeir N, Potti A, et al: Up-regulation of Wnt-1 and β-catenin production in patients with advanced metastatic prostate carcinoma: potential pathogenetic and prognostic implications. Cancer. 101:1345–1356. 2004.
11.	Zhang WM, Lo Muzio L, Rubini C and Yan G: Effect of WNT-1 on β-catenin expression and its relation to Ki-67 and tumor differentiation in oral squamous cell carcinoma. Oncol Rep. 13:1095–1099. 2005.
12.	Lee A, Raz DJ, He B and Jablons DM: Update on the molecular biology of malignant mesothelioma. Cancer. 109:1454–1461. 2007. View Article : Google Scholar : PubMed/NCBI
13.	Kim PJ, Plescia J, Clevers H, Fearon ER and Altieri DC: Survivin and molecular pathogenesis of colorectal cancer. Lancet. 362:205–209. 2003. View Article : Google Scholar : PubMed/NCBI
14.	Ma H, Nguyen C, Lee KS and Kahn M: Differential roles for the coactivators CBP and p300 on TCF/β-catenin-mediated survivin gene expression. Oncogene. 24:3619–3631. 2005.PubMed/NCBI
15.	He TC, Sparks AB, Rago C, et al: Identification of c-MYC as a target of the APC pathway. Science. 281:1509–1512. 1998. View Article : Google Scholar : PubMed/NCBI
16.	Husain AN, Colby TV, Ordonez NG, et al: Guidelines for pathologic diagnosis of malignant mesothelioma. Arch Pathol Lab Med. 133:1317–1331. 2009.PubMed/NCBI
17.	Attanoos RL and Gibbs AR: Pathology of malignant mesothelioma. Histopathology. 30:403–418. 1997. View Article : Google Scholar : PubMed/NCBI
18.	Nakano J, Huang C, Liu D, et al: The clinical significance of splice variants and subcellular localization of survivin in non-small cell lung cancer. Br J Cancer. 98:1109–1117. 2008. View Article : Google Scholar : PubMed/NCBI
19.	Katoh M, Kirikoshi H, Terasaki H and Shiokawa K: WNT2B2 mRNA, up-regulated in primary gastric cancer, is a positive regulator of the WNT-beta-catenin-TCF signaling pathway. Biochem Biophys Res Commun. 289:1093–1098. 2001. View Article : Google Scholar : PubMed/NCBI
20.	Zhang X, Gaspard JP and Chung DC: Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. Cancer Res. 61:6050–6054. 2001.PubMed/NCBI
21.	Lu CD, Altieri DC and Tanigawa N: Expression of a novel anti-apoptosis gene, survivin, correlated with tumor cell apoptosis and p53 accumulation in gastric carcinomas. Cancer Res. 58:1808–1812. 1998.PubMed/NCBI
22.	Kawasaki H, Altieri DC, Lu CD, Toyoda M, Tenjo T and Tanigawa N: Inhibition of apoptosis by survivin predicts shorter survival rates in colorectal cancer. Cancer Res. 58:5071–5074. 1998.PubMed/NCBI
23.	Mita AC, Mita MM, Nawrocki ST and Giles FJ: Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res. 14:5000–5005. 2008. View Article : Google Scholar : PubMed/NCBI
24.	Li F, Ambrosini G, Chu EY, et al: Control of apoptosis and mitotic spindle checkpoint by survivin. Nature. 396:580–584. 1998. View Article : Google Scholar : PubMed/NCBI
25.	Adams RR, Carmena M and Earnshaw WC: Chromosomal passengers and the (aurora) ABCs of mitosis. Trends Cell Biol. 11:49–54. 2001. View Article : Google Scholar : PubMed/NCBI
26.	Martinez A, Bellosillo B, Bosch F, et al: Nuclear survivin expression in mantle cell lymphoma is associated with cell proliferation and survival. Am J Pathol. 164:501–510. 2004. View Article : Google Scholar : PubMed/NCBI
27.	Shinohara ET, Gonzalez A, Massion PP, et al: Nuclear survivin predicts recurrence and poor survival in patients with resected nonsmall cell lung carcinoma. Cancer. 103:1685–1692. 2005. View Article : Google Scholar : PubMed/NCBI
28.	Brennan DJ, Rexhepaj E, O’Brien SL, et al: Altered cytoplasmicto nuclear ratio of survivin is a prognostic indicator in breast cancer. Clin Cancer Res. 14:2681–2689. 2008. View Article : Google Scholar : PubMed/NCBI
29.	Dang CV, Resar LM, Emison E, et al: Function of the c-Myc oncogenic transcription factor. Exp Cell Res. 253:63–77. 1999. View Article : Google Scholar : PubMed/NCBI
30.	Yang G, Timme TL, Frolov A, Wheeler TM and Thompson TC: Combined c-Myc and caveolin-1 expression in human prostate carcinoma predicts prostate carcinoma progression. Cancer. 103:1186–1194. 2005. View Article : Google Scholar : PubMed/NCBI
31.	Lu D, Kadota K, Ueno M, Nakashima N, Yokomise H and Huang CL: Adenoviral vector expressing short hairpin RNA targeting Wnt2B has an effective antitumour activity against Wnt2B2-overexpressing tumours. Eur J Cancer. Jun 4–2011, (Epub ahead of print).
32.	Rao DD, Vorhies JS, Senzer N, et al: siRNA vs. shRNA: similarities and differences. Adv Drug Deliv Rev. 61:746–759. 2009. View Article : Google Scholar : PubMed/NCBI
33.	Ma B, Zhang S, Jiang H, Zhao B and Lv H: Lipoplex morphologies and their influences on transfection efficiency in gene delivery. J Control Release. 123:184–194. 2007. View Article : Google Scholar : PubMed/NCBI
34.	Watanabe Y, Kojima T, Kagawa S, et al: A novel translational approach for human malignant pleural mesothelioma: heparanase-assisted dual virotherapy. Oncogene. 29:1145–1154. 2010. View Article : Google Scholar : PubMed/NCBI