Alterations of MEN1 and E-cadherin/β-catenin complex in sporadic pulmonary carcinoids

Veschi,Serena; Lattanzio,Rossano; Aceto,Gitana  Maria; Curia,Maria  Cristina; Magnasco,Salvatore; Angelucci,Domenico; Cama,Alessandro; Piantelli,Mauro; Battista,Pasquale

doi:10.3892/ijo.2012.1563

Alterations of MEN1 and E-cadherin/β-catenin complex in sporadic pulmonary carcinoids

Authors:
- Serena Veschi
- Rossano Lattanzio
- Gitana Maria Aceto
- Maria Cristina Curia
- Salvatore Magnasco
- Domenico Angelucci
- Alessandro Cama
- Mauro Piantelli
- Pasquale Battista
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Affiliations: Department of Experimental and Clinical Sciences, University ‘G. d'Annunzio’-Chieti-Pescara, I-66013 Chieti, Italy, Department of Medical, Oral and Biotechnological Sciences, University ‘G. d'Annunzio’-Chieti-Pescara, I-66013 Chieti, Italy, Division of Pathology, ‘SS. Annunziata’ Hospital, I-66013 Chieti, Italy, Department of Drug Sciences, University ‘G. d'Annunzio’-Chieti-Pescara, I-66013 Chieti, Italy
Published online on: July 20, 2012 https://doi.org/10.3892/ijo.2012.1563
Pages: 1221-1228
Copyright: © Veschi et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Pulmonary carcinoids, distinct in typical and atypical, represent 2-5% of all primary lung tumors. The aim of this study was to investigate the molecular alterations correlated with the development of this form of neoplasms. A collection of 38 paraffin-embedded apparently sporadic carcinoids was investigated, through a combined study, for protein expression/localization of menin, p53, β-catenin and E-cadherin and for mutational analysis of the MEN1, TP53 and CTNNB1 genes. Menin was expressed in 71% of cases, with a prevalent cytoplasmic (c) localization, β-catenin was expressed in 68.4% of cases, of which 36.8% with a membranous (m) and 31.6% with a cytoplasmic localization. Membranous E-cadherin immunoreactivity was detected in 84.2% cases, nuclear p53 expression in 5.3% of cases. Positive correlation was found between c-menin and c-β-catenin expression (rho=0.439, P=0.008). In addition, m-β-catenin showed a positive correlation with both c-β-catenin and E-cadherin expression (rho=0.380, P=0.022 and rho=0.360, P=0.040, respectively). With regard to the E-cadherin/β-catenin complex, we found also a significant positive correlation between c-menin and ‘disarrayed’ β-catenin expression (rho=0.481, P=0.007). MEN1 gene variants were characterized in 34% of cases. c-menin was more highly expressed in tumors with MEN1 variants, compared to tumors without MEN1 variants (P=0.023). Three nucleotide variants of TP53 were also detected. This study confirms the involvement of the MEN1 gene in the development of sporadic pulmonary carcinoids, demonstrates the accumulation of menin in the cytoplasm, and indicates that the disarrayed pattern of the complex significantly correlates with c-menin accumulation.

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1	Bini A, Brandolini J, Cassanelli N, Davoli F, Dolci G, Sellitri F and Stella F: Typical and atypical pulmonary carcinoids: our institutional experience. Interact Cardiovasc Thorac Surg. 7:415–418. 2008. View Article : Google Scholar : PubMed/NCBI
2	Travis WD, Brambilla E, Müller-Hermelink HK and Harris CC: WHO Classification of Tumors: Pathology and Genetics of Tumours of the Lung, Pleura,Thymus and Heart. IARC Press; Lyon: 2004
3	Travis WD, Rush W, Flieder DB, Falk R, Fleming MV, Gal AA and Koss MN: Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol. 22:934–944. 1998. View Article : Google Scholar : PubMed/NCBI
4	Hage R, de la Rivière AB, Seldenrijk CA and van den Bosch JM: Update in pulmonary carcinoid tumors: a review article. Ann Surg Oncol. 10:697–704. 2003. View Article : Google Scholar : PubMed/NCBI
5	Jeung MY, Gasser B, Gangi A, et al: Bronchial carcinoid tumors of the thorax: spectrum of radiologic findings. Radiographics. 22:351–365. 2002. View Article : Google Scholar : PubMed/NCBI
6	Debelenko LV, Brambilla E, Agarwal SK, et al: Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung. Hum Mol Genet. 6:2285–2290. 1976. View Article : Google Scholar : PubMed/NCBI
7	Lemos MC and Thakker RV: Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat. 29:22–32. 2008. View Article : Google Scholar : PubMed/NCBI
8	Travis WD, Rush W, Flieder DB, Falk R, Fleming MV, Gal AA and Koss MN: Bronchopulmonary neuroendocrine tumors. Cancer. 113:5–21. 2008. View Article : Google Scholar
9	Jiao Y, Shi C, Edil BH, et al: DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 331:1199–1203. 2011. View Article : Google Scholar : PubMed/NCBI
10	Corbo V, Dalai I, Scardoni M, et al: MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases. Endocr Relat Cancer. 17:771–783. 2010. View Article : Google Scholar
11	Kim H, Lee JE, Cho EJ, Liu JO and Youn HD: Menin, a tumor suppressor, represses JunD-mediated transcriptional activity by association with an mSin3A-histone deacetylase complex. Cancer Res. 63:6135–6139. 2003.PubMed/NCBI
12	Hughes CM, Rozenblatt-Rosen O, Milne TA, et al: Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol Cell. 13:587–597. 2004. View Article : Google Scholar : PubMed/NCBI
13	Yokoyama A, Wang Z, Wysocka J, et al: Leukemia protooncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol Cell Biol. 24:5639–5649. 2004. View Article : Google Scholar : PubMed/NCBI
14	Pelosi G, Scarpa A, Puppa G, et al: Alteration of the E-cadherin/β-catenin cell adhesion system is common in pulmonary neuroendocrine tumors and is an independent predictor of lymph node metastasis in atypical carcinoids. Cancer. 103:1154–1164. 2005.
15	Clavel CE, Nollet F, Berx G, et al: Expression of the E-cadherin/β-catenin complex in lung neuroendocrine tumours. J Pathol. 194:20–26. 2001.
16	Leotlela PD, Jauch A, Holtgreve-Grez H and Thakker RV: Genetics of neuroendocrine and carcinoid tumours. Endocr Relat Cancer. 10:437–450. 2003. View Article : Google Scholar : PubMed/NCBI
17	Zhuang Z, Vortmeyer AO, Pack S, et al: Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas. Cancer Res. 57:4682–4686. 1997.PubMed/NCBI
18	Catalano T, Curia MC, Aceto G, et al: Mutations in the p53 and Ki-ras genes, microsatellite instability and site of tumor origin in colorectal cancer. Oncol Rep. 14:625–631. 2005.PubMed/NCBI
19	Mahdavinia M, Bishehsari F, Verginelli F, et al: P53 mutations in colorectal cancer from northern Iran: Relationships with site of tumor origin, microsatellite instability and K-ras mutations. J Cell Physiol. 216:543–550. 2008. View Article : Google Scholar : PubMed/NCBI
20	Ng PC and Henikoff S: Accaounting for human polymorphisms predicted to affect protein function. Genome Res. 2:436–446. 2002.PubMed/NCBI
21	Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P and Olivier M: Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat. 28:622–629. 2007. View Article : Google Scholar : PubMed/NCBI
22	Bazzi W, Renon M, Vercherat C, et al: MEN1 missense mutations impair sensitization to apoptosis induced by wild-type menin in endocrine pancreatic tumor cells. Gastroenterology. 135:1698–1709. 2008. View Article : Google Scholar : PubMed/NCBI
23	Vogelstein B, Fearon ER, Hamilton SR, et al: Genetic alterations during colorectal-tumor development. N Engl J Med. 319:525–532. 1988. View Article : Google Scholar : PubMed/NCBI
24	Cho KR and Vogelstein B: Genetic alterations in the adenomacarcinoma sequence. Cancer. 70:1727–1731. 1992. View Article : Google Scholar : PubMed/NCBI
25	Goh HS, Yao J and Smith DR: p53 point mutation and survival in colorectal cancer patients. Cancer Res. 55:5217–5221. 1995.PubMed/NCBI
26	Sugio K, Osaki T, Oyama T, et al: Genetic alteration in carcinoid tumors of the lung. Ann Thorac Cardiovasc Surg. 9:149–154. 2003.PubMed/NCBI