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[Cancer Research 62, 7157-7161, December 15, 2002]
© 2002 American Association for Cancer Research

Advances in Brief

Identification of a Candidate Oncogene SEI-1 within a Minimal Amplified Region at 19q13.1 in Ovarian Cancer Cell Lines1

Terence C-M. Tang, Jonathan S. T. Sham, Dan Xie, Yan Fang, Ke-Ke Huo, Qiu-Liang Wu and Xin-Yuan Guan2

Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China [T. C-M. Y., J. S. T. S., X-Y. G.]; Department of Pathology [D. X.], and Cancer Institute [Y. F., Q-L. W.], Sun Yat-Sen University, Guangzhou, China; and State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai, China [K-K. H.]


   ABSTRACT
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 ABSTRACT
Introduction
 Materials and Methods
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 Discussion
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High-level amplification of DNA sequence at 19q13.1 is one of the frequent genetic alterations in ovarian cancer. In an attempt to verify the minimal amplified region (MAR) at 19q13.1 and to identify the target oncogenes, 49 probes within a region from D19S425 to D19S907 (~19.5 cM) were used to survey the amplification status in four ovarian cancer cell lines that have been confirmed as containing amplification at 19q13.1. Two separated overlapping MARs, MAR1 (~200 kb) and MAR2 (~1.1 Mb), were identified at 19q13.1. Two candidate oncogenes, AKT2 and SEI-1, were identified in MAR2. Amplification and overexpression of these two genes in four ovarian cancer cell lines were confirmed by Southern and Northern blot analyses. The proliferation-related function of AKT2 and SEI-1 suggests that both genes are likely to be biological targets of an amplification event at 19q13.1 in ovarian cancer and to play important roles in ovarian tumorigenesis.


   Introduction
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 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Ovarian cancer is the leading cause of death from female gynecological malignancies in developed countries, and its incidence has been increasing recently in Asian countries such as China and Singapore (1) . Because of its insidious onset, the disease is diagnosed in 70% of cases in an advanced stage. Like other solid tumors, the development of ovarian cancer is also considered as a long-term process that involves multiple genetic alterations. Frequent genetic alterations including the gains of 1q, 3q, 8q, 17q, 19q, and 20q and frequent losses of 4q, 13q, 16q, 17p, and 18q have been detected in ovarian cancer by CGH3 studies (2 , 3) .

Gene amplification and the consequent overexpression of the amplified oncogene is one of the common genetic alterations in various solid tumors that have been shown to play an important role in tumor pathogenesis, probably because the overexpression of the oncogene confers a growth advantage. Therefore, to identify commonly amplified chromosomal regions and the target oncogene within the regions it is imperative to understand the molecular mechanisms of the development and progression of cancer. In our previous study, the gain of 19q was detected in 12 (39%) of 31 primary ovarian cancers (3) . High copy-number amplification of 19q13.1-q13.2 in the form of a hsr has been observed in four ovarian cancer cell lines (UACC326, UACC1123, UACC2727, and OVCAR-3) by chromosome microdissection (4) . Although AKT2 has been implicated as a candidate oncogene at 19q13 (5) , coamplification of two or more oncogenes within one amplicon has been described previously. For example, chromosomal region 12q13-q15 has been shown to contain several genes, including MDM2, CDK4, GLI, SAS, and CHOP, that are potentially relevant to tumor growth. Coamplification and overexpression of CDK4, SAS, and MDM2 has been frequently detected in human parosteal osteosarcomas (6) . In addition, amplification of AKT2 was only detected in about 12–13% of primary ovarian cancers in a previous study (5) . Therefore, it is highly conceivable that one or more flanking oncogene(s) residing on either side of AKT2 could also contribute to the development of ovarian cancer. In the present study, we have applied the physical mapping strategy by using FISH and Southern Blot analysis to identify the overlapping MARs at 19q13.1-q13.2 in the above mentioned four ovarian cancer cell lines. The results showed that there are two separate MARs at 19q13.1, each of which may contain one or more oncogenes involved in the amplification events in ovarian cancer.


   Materials and Methods
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 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Cell Lines and DNA Isolation.
Ovarian cancer cell lines, UACC326, UACC1123, and UACC2727 were obtained from the Tissue Culture Core Service of the University of Arizona Comprehensive Cancer Center. Ovarian cancer cell line OVCAR3 was obtained from the American Type Culture Collection. Genomic DNA was extracted by a proteinase K/SDS digestion followed by phenol/chloroform/isoamyl alcohol extraction.

Probe Selection.
About 200 STS markers within the interested region of 19q13.1-q13.2 (from D19S425 to D19S907) were used as the initial starting point for probe selection. The genetic distance between D19S425 and D19S907 is about 19.5 cM (58.1–77.6 cM; GeneMap’99, NCBI). The sequences of STS markers were obtained from GeneMap’99, and BLAST search was performed to select corresponding cosmid clones for FISH study. Thirty cosmid clones were selected for FISH analysis and the distance between each other was ~1 cM. All of the cosmid clones were kindly provided by the Human Genome Center at Lawrence Livermore National Laboratory as free gifts. Thirteen known genes, one EST, and five unique genomic DNA sequences within the target region were selected to fill in gaps that could not be covered by cosmid clones. All of the cosmid clones and genes used in the present study are listed in Table 1Citation .


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  		Table 1 Summary of amplification pattern at 19q13.1 in four ovarian cancer cell linesa

MARs (MAR1, from sts-N29627 to Bda24b07; MAR2, from SGC32767 to sts-N31928) are shown in bold.

 
FISH.
Metaphases from four ovarian cancer cell lines were prepared for FISH analysis by a standard method. FISH was performed as described previously (7) . Briefly, 200 ng of purified cosmid DNA were labeled with Biotin-14-dCTP using BioPrime DNA labeling system (Life Technologies, Inc., Rockville, MD). About 100 ng of biotinylated probe was mixed in 10 µl of hybridization mixture (containing 55% formamide, 2x SSC, and 1 µg human Cot I DNA) which was denatured at 75°C for 5 min. The slide containing metaphases from tumor cells was denatured in 70% formamide, 2x SSC at 70°C for 2 min and hybridized with the denatured probe at 37°C overnight. After wash, the hybridization signal was detected by two layers of FITC-conjugated avidin (Vector Laboratories, Burlingame, CA) and amplified with one layer of anti-avidin antibody (Vector Laboratories, Burlingame, CA). The slides was counterstained with 0.5 µg/ml DAPI in an antifade solution and examined with a Zeiss Axiophot microscope equipped with a dual bandpass filter.

Southern and Northern Blot Analyses.
Southern blot hybridization was performed by a standard method. The PCR products of cDNA and unique genomic DNA sequences were labeled with [32P]dCTP using Random Labeling kit (Life Technologies, Inc., Rockville, MD). Fifteen µg of genomic DNA isolated from ovarian cancer cell lines were digested with EcoRI, fractionated on 1% agarose gel, transferred to a nylon membrane (Bio-Rad, Hercules, CA), and hybridized overnight at 42°C with 32P-probes. Ten µg of total cellular RNA, prepared by Trizol/chloroform method, were size fractionated on 1% agarose/2.2 M formaldehyde gel, transferred to a nylon membrane, and hybridized with 32P-probes.

Tissue Microarray.
A total of 200 epithelial ovarian cancer cases with 400 tissue specimens were obtained from the archives of Cancer Center, Sun Yat-sen University of Medical Sciences, Guangzhou, China. Two specimens, one from tumor tissue and the other from surrounding nontumor tissue, were selected. The tissue microarray was constructed as described previously (8) . Briefly, tissue cylinders with a diameter of 0.6 mm were taken from the selected regions of a donor block and then precisely punched into a recipient paraffin block using a tissue-arraying instrument (Beecher Instruments, Silver Spring, MD). Five-µm consecutive sections of the microarray block were made with a microtome.

Three cosmid clones, R31396 (mapped within MAR1), F23149 (within MAR2), F19514 (between the two MARs), were selected as FISH probes. The FISH reaction was performed as described previously (7) with some modifications. Briefly, the tissue array section was deparaffinized, treated with protenase K (400 µg/ml) at 37°C for 45 min, denatured at 75°C in 70% formamide, 2x SSC for 5 min, and hybridized with biotin-labeled cosmid probe at 37°C for 2 days. Washing condition and posthybridization treatment were identical as described above.


   Results
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Identification of Two MARs.
Thirty cosmid clones and 19 DNA sequences, which cover a genetic region of 19.5 cM (from D19S425 to D19S907) at 19q13.1-q13.2 were used to define the overlapping MAR among the four ovarian cancer cell lines by FISH and Southern hybridization, respectively. All four of the ovarian cancer cell lines used in this study were aneuploid and displayed chromosome numbers in the range of near-triploid except UACC1123, which was near-diploid. The degree of DNA amplification at 19q13.1 was divided into three levels according to the number of FISH signals and DNA amplification-fold detected by Southern hybridization, respectively. Low-level amplification (+) was defined as 2–5 extra FISH signals or 1–2-fold amplification of tested DNA sequences detected by FISH or Southern blot hybridization. Medium-level amplification (++) was defined as detection of 6–10 extra FISH signals or 2.5–4-fold amplification of tested DNA sequence. High-level amplification (+++) was defined as the detection of more than 10 extra FISH signals or 5-fold or more of amplification of tested DNA sequence. In this study, FISH signals in both metaphase chromosomes and interphase nuclei were counted. The extra FISH signals were determined based on the ploidy of each cell line. The amplification patterns of hsr detected by FISH and CGH in four ovarian cancer cell lines are shown in Fig. 1Citation .



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  		Fig. 1. FISH of cosmid clone (F23149) within MAR2 to metaphase spreads containing hsr markers in ovarian cancer cell lines UACC326 (A), UACC1123 (B), UACC2727 (C), and OVCAR-3 (D). Chromosomes (partial metaphases) were conterstained with DAPI (blue) and FISH signals (green); white arrows, hsr regions. Inset, the amplification of 19q13.1-q13.2 in each cell line detected by CGH.

 
Analysis results showed that the amplicons at 19q13.1 were not continuous in all four of the tested ovarian cancer cell lines, and two separate overlapping MARs (MAR1 and MAR2) were identified. The order of the STS markers corresponding to the cosmid clones and known genes were determined by searching NCBI Map Viewer (dated on August 30, 2002). MAR1 is ~207 kb (between 36,677 and 36,884 kb) and MAR2 is ~1124 kb (between 40,434 and 41,568 kb). The distance between MAR1 and MAR2 is ~3.5 Mb. The results were summarized in Table 1Citation .

Overexpression of AKT2 and SEI-1.
Candidate oncogenes within the MARs were screened through database search with NCBI Map Viewer. Several known genes were found in both MARs, including SUPT5H, SEI-1, GMFG, and AKT2 in MAR2. Amplification of these genes had been detected by Southern blot hybridization, and examples of amplification of AKT2 and SEI-1 are shown in Fig. 2ACitation . Among these genes, AKT2 and SEI-1 have been associated with cell proliferation and cell cycle control. Therefore, the RNA expression levels of these two genes were studied by Northern blot analysis to determine whether they were overexpressed in the tested ovarian cancer cell lines. The result showed that both AKT2 and SEI-1 were indeed overexpressed in all four of the ovarian cancer cell lines comparing with the total RNA from normal ovary (Fig. 2B)Citation .



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  		Fig. 2. Amplification and overexpression of AKT2 and SEI-1 in four ovarian cancer cell lines. In A, Southern blot analysis demonstrates amplification of AKT2 and SEI-1 in four ovarian cancer cell lines. A probe for ß-actin was used for loading control. B, overexpression of AKT2 and SEI-1 in ovarian cancer cell lines was detected by Northern blot analysis. Control RNA was from normal ovary. 28S RNA band stained with ethidium bromide for the Northern blot was used as loading control.

 
Tissue Microarray.
A tissue microarray section containing 400 specimens from 200 primary ovarian cancers was used to survey the amplification frequency of MAR1 and MAR2 at 19q13.1 in primary ovarian cancers. FISH hybridization was performed using cosmid clones R31396, F23149, and F19514 from MAR1, MAR2, and the low-amplified region between two MARs, respectively. FISH signals in 50 interphase nuclei were counted for each case. Informative FISH signals were observed in 103 of 200, 96 of 200, and 98 of 200 cases detected by R31396, F23149, and F19514, respectively. The noninformative samples might be caused by the missing of or unrepresentative tumor samples in the array section or failure of the detection. Amplification of DNA sequence in MAR1, MAR2, and region between the two MARs was detected in 17 (17%) of 101, 19 (20%) of 96, and 9 (9%) of 98 primary ovarian cancers, respectively (Fig. 3)Citation .



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  		Fig. 3. Tissue array for FISH analysis. A, overview of H&E-stained sections of tissue array containing 400 specimens from 200 primary ovarian cancers. B and C, two examples of amplification of DNA sequence within MAR2, detected with cosmid probe F23149. About 6–8 and >10 green signals were detected in case 71 (B) and case 122 (C), respectively. The interphase nuclei were conterstained with DAPI.

 

   Discussion
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Amplification of 19q13.1-q13.2 is one of the common genetic alterations in ovarian cancer, and overexpression of putative oncogene AKT2 at 19q13.1, which encodes a serine/threonine kinase, has been associated with the pathogenesis of ovarian cancer. Amplification of 19q13.1-q13.2 was also frequently detected in gastric cardia adenocarcinoma (9) and primary pancreatic carcinoma (10) . These studies strongly indicate that 19q13.1-q13.2 may contain an oncogene(s) related to the pathogenesis and progression of various solid tumors including ovarian cancer.

In this study, four ovarian cancer cell lines containing amplicon of 19q13.1-q13.2 in the form of hsr were characterized to define the overlapping MAR. Forty-nine cosmid clones and DNA markers within a 13.9-Mb region (average distance between two markers is ~280 kb) at 19q13.1 were selected to detect overlapping MARs. The resolution of markers selected in the critical region from stSG53555 to stSG12762 (36,333–42,426 kb; NCBI Map Viewer) is ~170 kb. The result showed that amplicons in all four cell lines were not continuous, and two separate overlapping MARs were identified. Our tissue microarray study also supported the observation that the amplification frequencies of MAR1 and MAR2 were obviously higher than those in the region between MAR1 and MAR2. The fact that a hsr can be composed of two or more separated DNA sequences from the same or different chromosomes has been demonstrated by chromosome microdissection in breast cancer (11) . In nine breast cell lines, 12 of 15 hsr markers were demonstrated to be composed of multiple chromosome components (11) . Other studies also observed extensive DNA rearrangements in N-myc amplicons in neuroblastoma (12) . These results indicate that the mechanism of hsr formation is very complex and might be associated with genomic instability.

The coamplification of two separated MARs in all four tested ovarian cancer cell lines suggests that the coamplification is not random. It is highly possible that the target genes located in these two regions may provide a stronger selective advantage to ovarian cancer progression. There is evidence that the existence of four independent amplified regions within 11q13 in breast cancer may provide potential coselection and synergistic role of different amplified genes (13) . Using interphase FISH technique, Tanner et al. (14) found three frequently coamplified regions at 20q11, 20q12, and 20q13.2 in breast cancer. Several candidate oncogenes have been considered as the biological target of amplification events, including ASC-2 (AIB 3) at 20q11 (15) , AIB1 at 20q12 (16) , ZNF217 and NABC1 at 20q13.2 (17) .

As expected, AKT2 was amplified in all four of the ovarian cancer cell lines and mapped in the overlapping MAR2. AKT2 is a serine-threonine kinase gene and frequently amplified in ovarian cancer (5) . The PI3K/AKT2 pathway has been demonstrated to be important in malignant transformation (18) . Another interesting candidate oncogene in MAR2 is SEI-1. Amplification and overexpression of SEI-1 has been demonstrated by Southern and Northern blot analyses. SEI-1 was recently isolated by yeast two-hybrid screening using p16INK4a as bait (19) . The SEI-1 gene encodes a Mr 34,000 protein (p34SEI-1), a CDK4-binding protein, which renders the activity of cyclin D/CDK4 resistant to the inhibitory effect of p16INK4a (19) . It is well known that the tumor-suppressing function of p16INK4a is through its binding to, and subsequent inhibition of, cyclin D 1/CDK4 kinase activity. Another study found that p34SEI-1 (also named TRIP-Br1) interacts with KRIP-1 (TIF1ß) and functionally contacts DP-1, stimulating E2F/DP-1 transcriptional activity (20) . These features suggest that SEI-1 is a candidate oncogene, and that its amplification may play an important role in the development and progression of ovarian cancer. Further study of genes within these two MARs may lead to the isolation of the oncogene(s) that is the biological target of the amplification event at 19q13.1 in ovarian cancer. In addition, the results in this study provide a useful basis for future studies of this region for understanding the molecular mechanisms of gene amplification and amplicon evolution in solid tumors.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by the Leung Kwok Tze Foundation and Chinese Visiting Scholar Foundation of Key Lab in University. Back

2 To whom requests for reprints should be addressed, at Department of Clinical Oncology, The University of Hong Kong, Room 109, School of Chinese Medicine, 10 Sassoon Road, Hong Kong, China; Fax: 852-28169126; E-mail: xyguan{at}hkucc.hku.hk Back

3 The abbreviations used are: CGH, comparative genomic hybridization; hsr, homogeneously staining region; MAR, minimal amplified region; FISH, fluorescence in situ hybridization; DAPI, 4',6-diamidino-2-phenylindole; STS, sequence tagged site; NCBI, National Center for Biotechnology Information. Back

Received 7/15/02. Accepted 10/30/02.


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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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