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Onc2010217.Pdf Oncogene (2010) 29, 4671–4681 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc ORIGINAL ARTICLE DEK oncoprotein regulates transcriptional modifiers and sustains tumor initiation activity in high-grade neuroendocrine carcinoma of the lung T Shibata1,2, A Kokubu1, M Miyamoto1, F Hosoda1, M Gotoh2, K Tsuta3, H Asamura4, Y Matsuno5, T Kondo6, I Imoto7,8, J Inazawa7,8 and S Hirohashi1,2 1Cancer Genomics Project, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan; 2Pathology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan; 3Clinical Laboratory Division, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan; 4Division of Thoracic Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan; 5Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan; 6Proteome Bioinfomatics Project, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan; 7Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan and 8Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone, Tokyo Medical and Dental University, Tokyo, Japan Lung cancer shows diverse histological subtypes. Large- Introduction cell neuroendocrine cell carcinoma and small-cell lung carcinoma show similar histological features and clinical Lung cancer is one of the most prevalent cancers behaviors, and can be classified as high-grade neuro- worldwide, and shows diverse histological subtypes, endocrine carcinoma (HGNEC) of the lung. Here we including adenocarcinoma, squamous cell carcinoma, elucidated the molecular classification of pulmonary large-cell carcinoma, large-cell neuroendocrine carcino- endocrine tumors by copy-number profiling. We compared ma (LCNEC) and small-cell lung carcinoma (SCLC; alterations of copy number with the clinical outcome of Travis and Brambilla, 2004). The latter two share HGNEC and identified a chromosomal gain of the DEK common histological features such as neuroendocrine oncogene locus (6p22.3) that was significantly associated differentiation and belong to a spectrum of endocrine with poor prognosis. We further confirmed that DEK neoplasms of the lung, which include benign (typical overexpression was associated with poor prognosis in a carcinoid; TC), intermediately malignant (atypical larger set of HGNEC. Downregulation of DEK by small carcinoid; AC) and highly malignant (LCNEC and hairpin RNA led to a marked reduction of in vitro colony SCLC) tumors (Travis et al., 1991; Travis and Brambil- formation, in vivo tumorigenicity and chemo-resistance, la, 2004). LCNEC and SCLC show similar clinical and was associated with loss of lung cancer stem cell behavior and can be classified as high-grade neuro- markers. Gene expression profiling revealed that DEK endocrine carcinoma (HGNEC; Asamura et al., 2006). downregulation was associated with altered expression of Genome-wide expression profiling has supported this transcriptional regulators, which specifically include classification, and led to the division of HGNEC into known targets of interchromosomal translocations in groups showing better and poor prognosis, showing no hematopoietic tumors, and knockdown of these epigenetic correlation with histological subtype (LCNEC or SCLC; modifiers affected colony formation activity. Our study Jones et al., 2004). However, details of the molecular showed that DEK overexpression, partly through an alterations in HGNEC, especially those associated with increase in its gene dose, mediates the activity of global malignant phenotypes, remain largely unknown. transcriptional regulators and is associated with tumor Recently, many studies have reported that a self- initiation activity and poor prognosis in HGNEC. renewing population of cancer cells, known as cancer Oncogene (2010) 29, 4671–4681; doi:10.1038/onc.2010.217; stem cell (CSC) or tumor-initiating cell, is responsible published online 14 June 2010 for histological heterogeneity, tumor recurrence, organ metastasis and drug resistance, which are hallmarks of Keywords: lung cancer; cancer stem cell; DEK; malignancy and related to poor prognosis (Visvader and neuroendocrine Lindeman, 2008). Interestingly, HGNEC is well known to frequently coexist with other histological subtypes such as adenocarcinoma or squamous cell carcinoma (so-called combined tumor; Travis and Brambilla, 2004), suggesting that this tumor contains a pluripotent stem cell-like population. Although several putative markers for lung cancer stem cells (such as CD133 and Correspondence: Dr T Shibata, Cancer Genomics Project, National ALDH1A) have been proposed (Peacock and Watkins, Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 2008), the molecular mechanisms responsible for main- 104-0045, Japan, E-mail: tashibat@ncc.go.jp taining these stem cell features are largely unknown. Received 29 September 2009; revised 26 April 2010; accepted 2 May To further understand the molecular mechanisms 2010; published online 14 June 2010 related to the progression of HGNEC, we have DEK oncoprotein in pulmonary endocrine carcinoma T Shibata et al 4672 compared copy-number alterations with clinical out- Thus, the copy number-based classification elucidated a come of HGNEC and shown that chromosomal gain of carcinoid subgroup, which contains all carcinoid sam- the DEK gene locus is significantly associated with poor ples and exceptionally one LCNEC case (Carcinoid prognosis. DEK was originally identified as a fusion branch in Figure 1b). Unsupervised classification partner of t(6;9)(p23;q34) translocation in a subtype of revealed three subclasses (HGNEC-BR1-3) in the acute myeloid leukemia; von Lindern et al., 1992) and is HGNEC group, suggesting of the possibility of mole- overexpressed in several types of solid tumor such as cular subtypes in HGNEC, and SCLC was significantly liver cancer (Kondoh et al., 1999; Carro et al., 2006; segregated in HGNEC-BR1 (P ¼ 0.00246). We then Khodadoust et al.,2009). performed extensive molecular characterization of the lung endocrine tumors by the immunohistochemical analysis of candidate tumor suppressor (p53, PTEN and Results RB) and oncogene (SKP2, EGFR, MET and KIT) products in this cohort (Figure 1b). Aberrant expres- Molecular classification of endocrine tumors of the lung sions of these proteins were more frequent in HGNEC, To clarify the chromosomal alteration profile of the but no significant correlation was observed among endocrine tumors of the lung, we performed array-based HGNEC-branches and oncoprotein expressions (data comparative genomic hybridization (CGH) analysis of not shown). Notwithstanding the inability to character- the 49 primary tumors (11 cases of TC, 2 cases of AC, 8 ize this classification by known molecular markers, cases of SCLC and 28 cases of LCNEC), which include when clinical outcome was compared, patients in samples analyzed in our previous report (Peng et al., HGNEC-BR2 showed a significantly better outcome 2005). We then conducted unsupervised cluster analysis than the others (HGNEC-BR1/3; Figure 1c and of the CGH data to examine whether histological Supplementary Figure 1), suggesting of novel molecular subtypes have any association with genomic classifica- markers that can discriminate the two groups. Then we tion (Figure 1a). As shown in Figures 1a and b, searched for the genetic differences between HGNEC- chromosome alterations in TC and AC are characteristic BR1/3 (poor prognosis) and HGNEC-BR2 (good and clearly distinct from those observed in HGNEC prognosis) and found that copy number alterations at (LCNEC and SCLC; distinctive bacterial artificial four loci (12q13 EPS8 (adjusted P ¼ 0.0033), 6p22.3 chromosome (BAC) clones between carcinoid and DEK (P ¼ 0.017), 2p24 NBAS (P ¼ 0.022) and 2q31.3 HGNEC are listed in the Supplementary Table 1). ITGA4 (P ¼ 0.046)) differed significantly between the Figure 1 Molecular classification of pulmonary endocrine tumors. (a) Hierarchical cluster analysis of pulmonary endocrine tumors based on the changes in copy number at 800 loci. Red indicates copy number gain/amplification and green indicates copy number loss. Color bars at the bottom show subgroups. (b) Association between immunohistological features and genetic classification in pulmonary endocrine tumors. Each column indicates a single primary tumor. In the histology row, blue, yellow, red and green boxes indicate TC, AC, LCNEC and SCLC, respectively. In the p53 row, solid and gray boxes indicate strong and moderate p53 protein expression, respectively, which are suggestive of mutant p53. In the PTEN and RB rows, solid box indicates loss of tumor-suppressor protein expression. In other rows, solid and gray boxes indicate strong and moderate oncoprotein expression, respectively. (c) Genetic classification of HGNEC is associated with clinical outcome by Kaplan–Meier analysis. (d) Significant difference in copy number of the DEK gene locus between HGNEC-BR1/3 and HGNEC-BR2. Oncogene DEK oncoprotein in pulmonary endocrine carcinoma T Shibata et al 4673 two groups. In this study, we focused on the DEK gene DEK expression such as that around small vessels, because it encodes a well-known leukemia oncoprotein. which has been suggested to represent a CSC niche in Analysis of other targets (EPS8 encoding an epidermal neural tumors (Calabrese et al., 2007), or a scattered growth factor receptor pathway substrate, and NBAS pattern within the
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