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10.1245/s10434-006-9121-x
Annals of Surgical Oncology 14:885-892 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Opa Interacting Protein 5 (OIP5) Is a Novel Cancer-testis Specific Gene in Gastric Cancer

Yoshito Nakamura1,2,3, Fumiaki Tanaka1,2, Hisashi Nagahara1,2, Keisuke Ieta1,2, Naotsugu Haraguchi1,2, Koshi Mimori1,2, Atsushi Sasaki1,2, Hiroshi Inoue1,2, Katsuhiko Yanaga3 and Masaki Mori1,2

1 Department of Surgery and Molecular Oncology, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumibaru, Beppu, 874-0838, Japan
2 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama, Japan
3 Department of Surgery, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, Japan

Correspondence: Address correspondence and reprint requests to: Masaki Mori; E-mail: mmori{at}beppu.kyushu-u.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Identification of novel cancer-specific antigens is important for the advancement of immunotherapy. Our aim was to identify cancer-specific genes in gastric cancer.

Methods: Using cDNA microarray analysis, we detected genes overexpressed specifically in gastric cancer cells. The expression levels of selected genes, including OIP5, was confirmed by real time RT-PCR analysis in tumor/normal paired bulk samples of 58 clinical cases. The expression levels of selected genes in normal tissues were also determined with a human total RNA master panel. We also compared the expression status of OIP5 with that of the other known cancer-testis specific genes.

Results: Twenty-two genes were determined to be upregulated in gastric cancer cells. Among these, three genes (CDC6, Exo1, and OIP5) were selected and confirmed to be up-regulated in the tumor tissue compared to normal tissue. A human total RNA master panel demonstrated that OIP5, but not Exo1 or CDC6, showed high specificity in testis. Thus OIP5 may be considered a cancer-testis specific gene. In 58 clinical cases of gastric cancer examined, we found OIP5 gene expression in 27 cases (47%). Thirteen of these 27 cases showed no expression of the known cancer specific genes such as MAGE-1, MAGE-3 or NY-ESO-1.

Conclusions: Using a combination of LMD and microarray, we identified OIP5 as a cancer-testis specific gene. Further expression analysis in a set of clinical cases revealed that OIP5 may be a novel immunotherapy target for patients with gastric cancer.

Key Words: OIP5 • PRAME • Gastric cancer • Laser micro dissection • Cancer testis antigen

Abbreviations: OIP5, Opa interacting protein • 5CTA, cancer testis antigen • GAPDH, glyceraldehyde 3-phosphate dehydrogenase • LMD, laser microdissection • RT-PCR, reverse transcriptase-polymerase chain reaction


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Gastric cancer is lethal if patients are not diagnosed at an early stage. A high incidence of gastric cancer persists in Japan, South America, and Eastern European countries. According to surveillance, epidemiology, and end results (SEER) data, an estimated 22,700 new cases of gastric cancer were diagnosed in the United States in 2004, and an estimated 11,700 patients died of gastric cancer,1 although therapies such as surgery and chemotherapy have improved. To improve the survival rates from gastric cancer, development of new treatments is crucial.

Immunotherapy, which utilizes tumor-specific peptides, RNA, or tumor lysate to target cancer cells, is now considered a viable therapeutic strategy against advanced cancers.2,3,4 MAGE was the first reported cancer-testis specific gene and is considered a target gene for cancer-specific immunotherapy.5 We previously reported that MAGE-1 and MAGE-3 genes are expressed in 62 and 57% of esophageal cancers, 30 and 20% of colorectal cancers, and 24 and 31% of breast cancers, respectively.6,7 We also identified MAGE-encoded peptides recognized by cytotoxic T lymphocytes (CTLs).8,9 Based on these findings, cancer-specific immunotherapy using the HLA class I restricted MAGE peptide is performed in our institute for patients with advanced cancers such as gastric, esophageal, or colorectal cancers.2 However, applications of this therapy are restricted by the expression of the MAGE gene in the tumor and the HLA type of the patient. Indeed, the expression of CTAs such as MAGE-1, MAGE-3, and NY-ESO-1 are not so frequently recognized in gastric cancer.10 Therefore, identification of additional new CTAs will expand the utility of cancer specific immunotherapy for gastric cancer.

Combining laser microdissection (LMD) and oligomicroarray, we identified 28 genes differentially expressed between gastric cancer cells and normal gastric epithelial cells to identify cancer specific genes. An ideal cancer-specific antigen for immunotherapy would be specifically and stably expressed in tumor cells but absent in normal cells except for testis. Therefore, we selected three genes, including OIP5, from the 28 differentially expressed genes, and confirmed our data by real-time semiquantitative RT-PCR in 58 clinical samples and a human normal tissue panel. OIP5 was expressed exclusively in testis, and we therefore discussed this as a cancer-testis specific gene and a potential target for cancer immunotherapy.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Clinical Samples
Samples of cancerous and non-cancerous tissues were isolated from 58 gastric cancer patients who underwent gastrectomy with lymph node dissection from 1999 to 2002 at Kyushu University Hospital at Beppu, Japan. All 58 patients in the study provided their informed written consent. The patients ranged in age from 48 to 84 years (mean, 69.8 years). None of the patients underwent preoperative chemotherapy and/or radiotherapy, and none had synchronous or multiple metastatic cancers in the other organs. Pathologically, all tumors were adenocarcinomas. The 58 tumor samples and the matched control samples taken from normal tissue located far from the gastric cancer were frozen in liquid nitrogen immediately and stored at –90°C until RNA extraction. In 6 out of 58 cases, additional tumor and normal tissue was obtained and embedded in Tissue Tek OCT medium (Sakura, Tokyo, Japan) for LMD and microarray analysis. The samples from six cases were analyzed independently. In the six cases, the original tumors of the four cases showed well differentiated adenocarcinomas, and those of the other two cases showed moderately differentiated adenocarcinomas.

LMD and Microarray Analysis
Preparation of Tissue Samples for LMD
Frozen tissues were sectioned by a cryostat (Leica Microsystems, Wetzlar, Germany) at 5 µm, mounted on glass slides and covered with PEN foil (2.5 µm thick; Leica Microsystems). The slice samples were quickly fixed using a mixture of 100% ethanol and acetic anhydride (19:1). Slides were stained with hematoxylin and eosin (H&E) and dehydrated with ethanol. The sections were microdissected using the LMD system (Leica LMD System, Leica Microsystems) (Fig. 1aGo). Total RNA was extracted using an RNeasy Mini Kit (Qiagen, Hiden, Germany) according to the manufacturer’s instructions. All total RNA extracted from cancer cells and non-cancerous tissue was assessed for quality by an Agilent 2100 Bioanalyzer (Agilent Technologies, Inc., USA) according to the manufacturer’s instructions. The samples from six cases were analyzed independently.


Figure 1
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  		FIG. 1. a An image of laser microdissection (LMD). Gastric cancer tissue before LMD (top) and after LMD (bottom). b Scatter plots of microarray analysis between cancer cells and non-cancerous gastric epithelial cells. The X- and Y-axis show intensity of Cy3 (normal tissue) and Cy5 (cancer tissue), respectively.

 
T7-based RNA Amplification and Labeling
Total RNA was obtained from integrated laser microdissected cancer cells (50 ng) and non-cancerous gastric epithelial cells (50 ng). We carried out T7-based RNA amplification using the Low RNA Input Fluorescent Linear Amplification Kit (Agilent Technologies, Inc.). Total RNA from cancer cells and non-cancerous cells in six cases was amplified and reverse transcribed to cDNA by MMLV-RT using an oligo dT primer that incorporated a T7 RNA polymerase promoter. These cDNAs were used as templates for in vitro transcription reactions in the presence of Cyanine labeled CTPs (NEN Life Science, Boston, MA, USA) by T7 RNA polymerase. The cDNA of the non-cancerous epithelial cells was labeled with Cyanine 3-CTP (Cy3) and cDNA from the cancer cells in each case was labeled with Cyanine 5-CTP (Cy5). Labeled complementary RNA (cRNA) samples were purified using an RNeasy Mini Kit. After purification, qualities of cRNA were re-evaluated on the Agilent 2100 Bioanalyzer.

Microarray Hybridization and Scanning
The Cy3 and Cy5 labeled cRNA targets and control targets were mixed and hybridized with the Human 1A Oligo Microarray (Agilent Technologies, Inc.).11 Samples were hybridized in an Agilent hybridization chamber (Agilent Technologies, Inc.) at 60°C for 17 h. Slides were then removed from the chamber and washed and dried by using the In situ Hybridization kit-plus (Agilent Technologies, Inc.) according to the Agilent array protocol. Immediate scanning of slides was performed with the Agilent dual laser DNA microarray scanner (Agilent Technologies, Inc.) (Fig. 1bGo).

Data Analysis
The intensity of each hybridization signal was evaluated using Feature Extraction software (Agilent Technologies, Inc.). A common logarithm of the Cy5/Cy3 ratio for each sample was calculated by averaging the spots. A cutoff value for expression level was automatically calculated according to the background fluctuation. Normalization of expression was performed using LOWESS normalization.12 Rosetta Luminator software (Rosetta Biosoftware, Kirkland, USA) was used to analyze gene expression data.

Evaluation of the Selected Gene Expressions in the Clinical Samples and the Normal Tissue Panel
Gene expression of selected genes was examined in 58 clinical cases and Human Total RNA Master Panel (Cat# 636643, Clontech, Palo Alto, CA, USA) using real-time semiquantitative RT-PCR. Total RNA was extracted from each sample and cDNA was synthesized from 8.0 µg total RNA as described previously.13 The glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene served as an internal control. The oligonucleotide primers designed for selected genes and PCR conditions are shown in Table 1Go. PCR reactions were performed in a Light-CyclerTM system (Roche Applied Science, India-napolis, IN, USA) using the LightCycler-FastStart DNA Master SYBR Green I Kit (Roche Applied Science) as described previously.14 After PCR, electrophoresis on 2% agarose gels was performed to ensure the generation of the expected PCR products. Gene expression levels of CDC6, OIP5, and Exo1 were compared to that of cDNA from Human Universal Reference RNA (Cat# 636538, Clontech). To analyze whether OIP5 was expressed synchronously with already known CTA genes, we evaluated the expression of OIP5, MAGE-1, MAGE-3, and NY-ESO-1 genes by RT-PCR using the conditions shown in Table 1Go.


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  		TABLE 1. Sequence of PCR primers
 
Statistical Analysis
All statistical analyses were performed using the JMP 5 for Windows software (SAS Institute Inc. Cary, NC, USA). The associations between clinicopathological features and OIP5 expression levels were calculated with nonparametric Kruskal-Wallis and Mann–Whitney U tests. A P value of <0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Identification of Overexpressed Genes by Microarray
Each cDNA probe was hybridized to an oligomicroarray with 17,086 genes. Figure 1bGo shows scatter plots of microarray analysis comparing cancer cells and non-cancerous gastric epithelial cells in one representative case.

Twenty-eight genes were overexpressed two or more fold in the cancer cells compared to normal gastric epithelial cells in four of six cases (Table 2Go). The average fold change of selected genes was 2.99.


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  		TABLE 2. A list of overexpressed genes in gastric cancer cells
 
Gene Expression in Clinical Samples and Human Total RNA Master Panel
For further analysis of genes identified by microarray analysis, real-time semiquantitative RT-PCR was performed in 58 paired samples with respect to the three genes. The three genes we selected, cell division cycle 6 (CDC6), exonuclease 1 (Exo1), and Opa interacting protein 5 (OIP5), have not been previously reported in gastric cancer. All three of these genes were confirmed to be overexpressed in tumor tissue compared to the normal tissue (Fig. 2Go). There was no correlation between expression of these genes and clinicopathological factors such as age, depth of tumor invasion in the wall, lymph vessel permeation, vascular vessel permeation, lymph node metastasis or prognosis (data not shown).


Figure 2
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  		FIG. 2. Real-time semiquantitative RT-PCR analysis of three genes of Exo1, CDC6, and OIP5 in 58 cases of gastric cancer. These three genes were overexpressed in tumor tissue compared to the normal tissue. Six LMD cases are shown by circle. *P < 0.05 ** P < 0.01.

 
Real-time semiquantitative RT-PCR was performed in the human total RNA master panel to evaluate expression of CDC6, Exo1, and OIP5 in normal tissue. CDC6 and Exo1 are strongly expressed in bone marrow, testis and placenta and weakly expressed in colon, stomach and small intestine (data not shown). OIP5 is expressed at a high level only in testis (Fig. 3Go). OIP5 expression was weakly recognized in bone marrow, colon, and small intestine, however the quantity of expression was negligible.


Figure 3
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  		FIG. 3. Human total RNA Master Panel analysis of OIP5 gene. The expressions of OIP5 mRNA was recognized in testis. Very weak expression is seen in bone marrow, colon, and small intestine, but is negligible.

 
Correlation of OIP5 Gene Expressions and Already Known CTA Genes
We previously reported that known CTAs are expressed synchronously in many cases,15 which limits the treatment targets of immunotherapy and obstructs treatment adaptation. Therefore, we performed RT-PCR and analyzed the correlation of OIP5 gene expression and already known CTA gene expression (MAGE-1, MAGE-3, and NY-ESO-1) in 58 cases of gastric cancer. Expression of any known CTA gene was observed in 21 out of 58 cases (36.2%), and among the 21 cases, 14 cases expressed the OIP5 gene synchronously. Expression of the OIP5 gene was found in 13 of 37 samples (35.1%) without known CTA gene expression. Consequently, 34 cases (58.6%) showed the expression of known CTA genes or the OIP5 gene (Fig. 4Go).


Figure 4
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  		FIG. 4. Correlation of OIP5 gene expression with already known CTA genes expression (MAGE-1, MAGE-3, and NY-ESO-1) in 58 cases of gastric cancer. The X-axis shows percentage of gastric cancer cases. The expression of any of the known CTA genes was recognized in 21 of 58 samples (36.2%), and the positive expression cases increased to 34 (58.6%) when OIP5 gene is considered.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In our institute, a clinical trial of cancer-specific immunotherapy has been ongoing on patients with gastrointestinal cancers, using antigen-presenting cells pulsed with MAGE peptides. Positive results were observed in some clinical cases, however, problems still exist. One of the issues is the restriction of candidates from immunotherapy. Prerequisites for therapy are MAGE gene expression in tumor tissues and the adaptation of patient HLA type to peptide-binding specificity. Another caveat to therapy is the heterogeneous expression pattern of MAGE, which may be a strategy for evasion of immunosurveillance by malignant cells.16,17

In this study, we performed DNA microarray analysis and identified 28 genes upregulated in gastric cancer tissues compared to normal tissues. Among these genes, the expression of S100A2, S100A7 and synuclein gamma was previously reported in several cancers,18,19,20 including gastric cancer.21,22 S100A2 and S100A7 are known to regulate cell growth and motility, cell cycle regulation, transcription, and differentiation.23 Synuclein-gamma enhances motility and invasiveness and increase metastasis in cancer cell lines.24 Furthermore, we discovered that the OIP5 gene is expressed in gastric cancers, but not in normal tissues except for testis. This finding suggests that OIP5 antigen might be a novel target for cancer immunotherapy in addition to MAGE-1 and MAGE-3. Moreover, expression of the OIP5 gene was detected in cases without expression of known CTA genes. OIP5 expression was observed in 13 of 37 gastric cancer cases (35.1%) that did not express MAGE-1, MAGE-3 or NY-ESO-1. The ratio of cases with expression of any known CTA gene or the OIP5 gene was 58.6% (34 of 58 cases), while the ratio of cases with expression of only a known CTA genes was 36.2% (21 of 58 cases) (Fig. 4Go). This result suggest that OIP5 could be a new candidate target antigen in addition to MAGE-1, MAGE-3 and NY-ESO-1 for CTA-based cancer immunotherapy for gastric cancer.

In this study, there was no correlation between OIP5 expression and clinicopathological factors and prognosis (data not shown), similar to MAGE gene expression.6,8,22 OIP5 is homologous to an isolate from the same human testis cDNA library described for OIP4,23 which is identical to preferentially expressed antigen of melanoma (PRAME).26 OIP5 is one of the human epithelial cell proteins that interacts with Opa proteins which is an outer membrane proteins in human cells that participates in adhesion and invasion of gonococcus.25 However, the details of OIP5 are unknown. Recently, several reports of PRAME expression in cancers have been published.11,26–30 A downregulation of PRAME seems to be associated with poor prognosis,31,32 and an over-expression of PRAME induces apotosis of leukemic cells.33 While OIP5 is not identical to PRAME, these reports could be helpful in understanding the function of OIP5, and further functional analyses will elucidate OIP5’s exact role.

In summary, OIP5 is a potential target for cancer-specific immunotherapy in addition to known genes such as MAGE. Furthermore, OIP5 could be a novel target for cases that do not express MAGE-1, MAGE-3, and NY-ESO-1 in gastric cancer.


   ACKNOWLEDGMENTS
 
We thank Ms. T. Shimooka, Ms. K. Ogata, Ms. M. Oda, Ms. N. Kasagi, and Ms. Y. Nakagawa for their excellent technical assistance.


   FOOTNOTES
 
Grant sponsors: CREST, JST; Uehara Memorial Foundation; Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research, grant numbers 17015032, 17109013, 17591411, 17591413, and 16390381; Health and Labour Sciences Research Grants; Third Term Comprehensive Control Research for Cancer, 16271201.

Received for publication May 29, 2006. Accepted for publication June 5, 2006.


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 MATERIALS AND METHODS
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 DISCUSSION
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