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Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical & Dental University, Tokyo 113-8510, Japan [I. I., Z-Q. Y., A. P., J. I.]; Second Department of Pathology, National Defense Medical College, Saitama 359-8513, Japan [H. T.]; Department of Surgery, Surgically Basic Medicine, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan [Y. S., M. I.]; and Cancer Genomics Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan [M. O.]
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Introduction |
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Oncogenes, such as EGFR (7p12), MYC (8q24), and CCND1 (11q13), have already been identified as amplification targets associated with development, progression, or metastasis of ESCs3 (2, 3, 4) . Additional chromosomal amplicons have been identified in ESCs by means of CGH analysis (5, 6, 7) , although the target genes for those amplicons remain largely unknown. If we are to achieve novel insights into the pathogenesis of ESC and design improved protocols for its clinical management, candidate genes within these amplicons must be explored and characterized.
Our CGH analyses have revealed amplification at 11q21-q23 in ESC cell lines (7) and in primary ESC tumors (5) . This amplicon is of particular interest because, although infrequent, amplification within this region has been implicated in various other malignancies, including medulloblastoma (8) , renal-cell carcinoma (9 , 10) , glioblastoma (11) , and gastric cancer (12) . Therefore, this region may harbor gene(s) that, when activated by the amplification mechanism, are involved in carcinogenesis regardless of the type of tissue involved, although no specific gene has been proposed as a target.
In the study reported here, we performed a detailed molecular characterization of the 11q21-q23 amplicon using ESC cell lines, with the goal of identifying gene(s) involved in tumorigenesis. By determining levels of amplification and expression of 12 transcribed elements located in this amplicon, we successfully identified one candidate, cIAP1, a gene that encodes an antiapoptotic molecule. Cell lines that overexpressed this gene were resistant to the apoptosis induced by chemotherapeutic reagents. Because any mechanism that aberrantly prolongs the life span of a cell may contribute to carcinogenesis, our findings indicate that cIAP1 is a potential target for 11q21–23 amplification on the basis of both position and function.
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Materials and Methods |
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ESC tumor samples from 42 patients were provided by the Kyoto University Hospital, with written consent from each patient in the formal style and after approval by the local ethics committee.
FISH.
Metaphase chromosome slides were prepared, and FISH experiments were carried out in the manner described previously (14
, 15)
. The locations of BACs (RPCI-11 library) within the region of interest were compiled from information archived by the UCSC4
and the National Center for Biotechnology Information.5
Relative positions of the selected BACs on a map of the 11q22 region are indicated in Fig. 1
. Probes were labeled by nick-translation with biotin-16-dUTP or digoxigenin-11-dUTP (Roche Diagnostics, Tokyo, Japan). Chromosomal in situ suppression hybridization and fluorescent detection of hybridization signals were carried out as described elsewhere (14
, 15)
. The copy number and molecular organization of the region of interest were assessed according to the hybridization patterns observed on both metaphase and interphase chromosomes. Precise localization of each BAC was confirmed using normal metaphase chromosomes.
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; Table 1
). ATM (cDNA probe: clone 1367928) telomeric to the 11q22 amplicon was used as a reference in each analysis (Fig. 1A)
. For Southern blots, 10 µg of genomic DNA from each cell line or from normal lymphocytes were digested with EcoRI and separated on 0.8% agarose, then transferred onto a nylon membrane (BIODYNE B; Nihon Pall, Tokyo, Japan). For analyzing primary ESC tissues, we prepared Southern blots with 5 µg instead of 10 µg of genomic DNA or used dot blots, because the amount of available DNA was limited. For dot blots, 2 µg of DNA from each tumor, cell line, or normal lymphocyte was denatured with 0.4 N NaOH, then transferred to a nylon membrane (BIODYNE B; Nihon Pall). For Northern blots, 10 µg of total RNA extracted from each cell line was electrophoresed in a 1.0% agarose/0.67 M formaldehyde gel and transferred to a positively charged nylon membrane (Hybond N+; Amersham Pharmacia Biotech, Tokyo, Japan). Membranes were hybridized under appropriate conditions with [
32P]-dCTP-labeled cDNA probes prepared from expressed-sequence tag clones (Table 1)
purchased from Incyte Genomics, Inc. (St. Louis, MO). The blots were washed in a solution of 0.1XSSC/0.1% SDS before exposure to X-ray film for 24–84 h at -80°C.
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Expression of cIAP1 protein in formalin-fixed, paraffin-embedded tissue sections from primary ESC tumors was detected by indirect IHC, as described elsewhere (18) . Dewaxed and rehydrated sections were incubated in 3% hydrogen peroxide to block endogenous peroxidase, then reacted overnight at 4°C with 0.67 µg/ml antihuman cIAP1 polyclonal antibody (H-83) or normal rabbit serum. After rinsing, the sections were incubated with rabbit EnVision+ peroxidase (Dako, Carpinteria, CA), and staining was developed with 0.05% hydrogen peroxide and 3,3'-diaminobenzidine. The sections were counterstained with hematoxylin.
Estimation of Viability and Apoptotic Cell Death.
Sensitivity of ESC cells to cDDP or CPT was assessed using a colorimetric assay on microtiter plates (cell-counting kit-8; Dojindo Laboratories, Kumamoto, Japan), which measures the ability of viable cells to cleave a tetrazolium salt (WST-8) to a water-soluble formazan. In brief, cells were seeded at 104 cells/well in 96-well plates. After plating (24 h), cells were exposed to various concentrations of cDDP or CPT for 48 h. WST-8 was added 2 h before the end of culture, and absorbance was measured at 450 nm using a microplate reader (Benchmark; Bio-Rad Laboratories, Hercules, CA). Experiments were repeated three times, and each series was performed in triplicate.
For nuclear staining, cells were plated onto glass coverslips and incubated with or without 10 µg/ml cDDP or CPT for 24 h. Cells were washed, fixed, and stained with DAPI. Nuclear morphology was examined with a fluorescence microscope (Nikon).
For observation of DNA fragmentation, cells were plated on 60-mm dishes and incubated with or without 10 µg/ml cDDP or CPT for 24 h. DNA was extracted from washed cells with the Quick Apoptosis DNA Ladder Detection Kit (Medical & Biological Laboratories, Nagoya, Japan), separated through a 2% agarose gel, and visualized after staining with ethidium bromide.
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. We assessed the copy number as well as molecular organization of the amplicon by analyzing the hybridization patterns on metaphase and interphase chromosomes.
In both cell lines, five BACs (21G19, 864G05, 750P05, 686G06, and 23P06) produced the highest number of signals as HSRs on two marker chromosomes (Figs. 1B
and 2
). By contrast, no HSR pattern and less than two FISH signals on each marker chromosome were detected with eight other BACs (391A04, 26C09, 49M09, 103C15, 130N12, 20H14, 212N01, and 241D13), suggesting that these eight lay outside the amplicon. The remaining seven BACs examined (40B14, 265O01, 681O17, 236L10, 748H22, 2I22, and 37O16) demonstrated different patterns and/or numbers of signals between KYSE170 and KYSE2270, but all of them showed fewer signals than BACs 21G19, 864G05, 750P05, 686G06, or 23P06 on each marker chromosome in at least one cell line. Taken together, as summarized in Fig. 1
, we defined the SRO between BACs 21G19 and 23P06. The estimated extent of this region was 1.8 Mb on 11q22, on the basis of the genome database archived by the UCSC.
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; Table 1
). Among them, only cIAP1 was consistently overexpressed in the two cell lines that showed amplification (Fig. 3)
, strongly suggesting that this gene is a potential target within the 11q22 amplicon. On the other hand, MMP10 and MMP13 were highly expressed in KYSE2270 but not in KYSE170 (Fig. 3B)
. None of the remaining genes within the SRO, including cIAP2 and the uncharacterized transcript, were overexpressed in both cell lines (data not shown). Therefore, none of the examined transcripts, except for cIAP1, are likely to be targets for 11q22 amplification.
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. Cell lines without amplification of cIAP1 showed a considerably lesser degree of cytoplasmic staining for this molecule, in accord with the results of Northern blotting (Fig. 3C)
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Next, we performed IHC analysis of cIAP1 using tissue sections of the primary ESC tumors from which the KYSE series of ESC cell lines had been established. As shown in Fig. 3D
, moderate to strong staining of cIAP1 was clearly observed in >10% of cancer cells but not in normal epithelial or stromal cells in parent tumors of the KYSE 170 and 2270 lines. In both primary tumors, most immunoreactions occurred in the cytoplasm of cancer cells, at the frontier of stromal invasion. The cIAP1-immunopositive carcinoma cells were usually pleomorphic; they infiltrated into the stroma as single cells or in the form of small nests or strands. In the primary tumor of KYSE2270, strong cIAP1 staining was predominant at the periphery of the small nests (Fig. 3D
, right panel). By contrast, we detected no or weak staining of cIAP1 in primary ESC tumors of KYSE cell lines without 11q22 amplification or in breast tumors used as controls (data not shown). These results strongly suggest that amplification of the cIAP1 gene, resulting in overproduction of this protein, had already occurred in the primary tumors, from which KYSE 170 and 2270 were derived.
Resistance of ESC Cell Lines with Amplified cIAP1 to Drug-induced Apoptosis.
Because cIAP1 is a member of the IAP family of proteins, and because some IAPs are thought to be involved in carcinogenesis through their antiapoptotic activity (19)
, we investigated whether the two ESC cell lines with amplification of cIAP1 were resistant to apoptotic stimuli. As shown in Fig. 4A
, both KYSE 170 and 2270 exhibited resistance to cDDP and CPT as compared with control cell lines (KYSE200 and 960) in which cIAP1 was not overexpressed. The resistance of KYSE170 and 2270 cells to these anticancer drugs may reflect resistance to chemotherapeutic agent-induced apoptosis, because 10 µg/ml cDDP or CPT induced remarkable apoptotic changes in control cells but had little effect on KYSE 170 or 2270 cells. As shown in Fig. 4 (B and C)
, typical apoptotic changes, such as condensation of nuclear chromatin and laddering of DNA, were observed in KYSE 200 after 24 h of treatment with cDDP. In KYSE170 (data not shown) and 2270 cells, however, few apoptotic cells and little fragmented DNA were observed after the same treatment. The same results were obtained with CPT (data not shown).
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Discussion |
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As the first step in exploring the 11q21-q23 region for candidate genes, we constructed a map of the amplicon by FISH to define a relatively small chromosomal region that would make a positional search possible. The criterion we used to define the amplicon is that the best candidate tumor-associated genes, which are selected during amplification process, are located at narrow regions of highest copy number (22) . Our determination of the SRO using this criterion and two different cell lines helped to narrow even further the region likely to harbor target gene(s). Even after defined mapping, however, many genes must still exist on an amplicon. The common criterion for designating a gene as a putative target is that amplification leads to its overexpression (23 , 24) . On the basis of that criterion, we used Northern blots to identify transcripts that were consistently overexpressed in two ESC cell lines where the defined region at 11q22 was amplified (KYSE 170 and 2270) and successfully identified cIAP1 as a strong candidate target for this amplification. Amplification of cIAP1 was detected as well in 4 of 42 unrelated primary ESC tumors, indicating that this genetic alteration is not cell line specific.
The cIAP1 gene product, designated variously as HIAP2, AIP1, MIHB, or BIRC2, was originally identified as a protein recruited to the cytosolic domain of p80 tumor necrosis factor II via its association with tumor necrosis factor-associated factors-1 and -2 (25)
. cIAP1 protein, like cIAP2 and XIAP in the same subfamily of IAPs, contains three baculovirus IAP repeat domains in the NH2-terminal region and a RING (real interesting new gene) finger domain close to the COOH terminus. Ectopic expression of cIAP1 in mammalian cells can inhibit apoptosis induced by serum deprivation or by a variety of stimuli (19
, 26)
. Consistent with those published observations, our ESC cell lines showing amplification of cIAP1 were resistant to apoptosis induced by chemotherapeutic agents. Our preliminary study demonstrated that those cell lines with amplification of cIAP1 were also resistant to apoptosis induced by radiation, suggesting that overexpressed cIAP1 inhibits apoptosis, regardless of the type of apoptosis-inducing stimulus.6
Although the mechanism by which cIAP1 suppresses apoptosis is still debated, several studies have provided insights into the biochemical functions of this intriguing protein (19)
. The central mechanism appears to be direct inhibition of caspase and procaspase; cIAP1 binds directly to caspases 3 and 7 (27
, 28)
and also inhibits activation of procaspases 8 and 9 (29
, 30)
. cIAP1 appears to inhibit apoptosis through noncaspase mechanisms as well, e.g., by activation of nuclear factor 
B (30)
and c-Jun-NH2-terminal kinase (31)
.
Although evidence for a direct oncogenic role for cIAP1 has yet to emerge, our results indicate that this potent regulator of cell death is likely to play an important role in carcinogenesis. Inhibition of, or increased resistance to, apoptosis is a common property of cancer cells, as it increases their survival time and facilitates their escape from immune surveillance and cytotoxic therapies (19) . Therefore, a constitutive activation of antiapoptotic molecules via genetic or epigenetic mechanisms, including gene amplification, may well be involved in carcinogenesis. In follicular and diffuse large B-cell types of non-Hodgkin’s lymphoma, e.g., overexpression of BCL2 through amplification or translocation appears to be associated with progression of the disease (32 , 33) . Moreover, survivin, another member of the IAP family that is not expressed in normally differentiated tissues, is specifically overexpressed in some cancers (34) . Tamm et al. (35) reported that cIAP1 was expressed in most of the cancer cell lines they tested (a panel of 60 human cancer cell lines maintained by the National Cancer Institute), and its expression level was correlated with resistance to several anticancer drugs. Those results and our present findings encourage additional investigation of the functional role of cIAP1 in the genesis of various types of cancer, including ESC, as well as its prognostic relevance.
Our immunocytochemical study using ESC cell lines clearly showed that the amplification mechanism activated cIAP1 and led to overproduction of its product. Moreover, our immunohistochemical study of the archived primary tumors from which those lines had been established indicated that activation of cIAP1 via gene amplification had already occurred in vivo. We infer that activated cIAP1 might confer malignant phenotypes, including invasiveness, metastasis, and drug resistance. The cIAP1-immunopositive cancer cells were observed at the frontier of stromal invasion, and they proliferated into the stroma as single cells or in the form of small nests or strands. These findings suggest that increased immunoreactivity of cIAP1 may reflect a highly invasive potential of ESC cells. Ono et al. (36)
observed a similar pattern of immunohistochemical staining for laminin-5 
2 chain in squamous cell carcinomas of the tongue. Their analysis of 67 such tumors demonstrated that strong cytoplasmic localization of the laminin-5 2 chain was significantly associated with poor prognosis for patients with squamous cell carcinomas of the tongue (36)
. Accordingly, it will be important to determine the clinicopathological significance of cIAP1 expression in squamous cell carcinomas arising in other organs as well as the esophagus.
Of the 12 transcripts we screened, 11 were excluded as candidates because they were not detectably or consistently expressed in the panel of ESC cell lines we examined. However, of the excluded candidates, cIAP2, which encodes another member of the IAP family, has been identified as a target gene at the breakpoint of a translocation observed often in MALT-type lymphomas (37, 38, 39) . In MALT lymphomas, cIAP2 is fused to MALT1, and the chimeric product may be involved in enhanced resistance to apoptosis, although its actual function remains unknown. However, cIAP2 was not overexpressed in any of cell lines we tested, including the two lines having 11q22 amplification. MMP-10 (stromelysin-2) and MMP-13 (collagenase-3) were each highly expressed in only one (KYSE2270) of those two cell lines, although MMP-10 and MMP-13 are often overexpressed in tumor cells, and that feature is correlated with tumor invasion and aggressiveness, respectively (40 , 41) . Expression of MMP-10 and/or MMP-13 may be inhibited in KYSE170 by some mechanism, possibly epigenetic. Thus, additional functional and biochemical studies might be needed to absolutely exclude these two genes as amplification targets.
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FOOTNOTES |
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1 Supported by Grants-in-Aid for Scientific Research on Priority Areas (C) from the Ministry of Education, Culture, Sports, Science and Technology, Grants-in-Aid from the Ministry of Health and Welfare of Japan, and in part by a grant from the Organization for Pharmaceutical Safety and Research. 
2 To whom requests for reprints should addressed, at Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. Phone: 81-3-5803-5820; Fax: 81-3-5803-0244; E-mail: johinaz.cgen{at}mri.tmd.ac.jp
3 The abbreviations used are: ESC, esophageal squamous cell carcinoma; CGH, comparative genomic hybridization; FISH, fluorescence in situ hybridization; BAC, bacterial artificial chromosome; DAPI, 4',6'-diamidino-2-phenylindole; HSR, homogeneously staining region; FIC, fluorescent immunocytochemistry; IHC, immunohistochemistry; UCSC, University of California at Santa Cruz; cDDP, cis-platinum; CPT, camptothecin; SRO, smallest amplified region of overlap; IAP, inhibitor of apoptosis; MALT, mucosa-associated lymphoid tissue; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.
4 Internet address: http://genome.ucsc.edu/.
5 Internet address: http://www.ncbi.nlm.nih.gov/.
6 I. Imoto et al., unpublished data.
Received 5/ 1/01. Accepted 7/31/01.
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-interferon therapy for Ph positive chronic myelocytic leukemia. Cancer Genet. Cytogenet., 81: 20-23, 1995.[Medline]
B antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science (Wash. DC), 281: 1680-1683, 1998.2 chain expression in squamous cell carcinoma of the tongue: immunohistochemical analysis of 67 lesions. Cancer (Phila.), 85: 2315-2321, 1999.[Medline]
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