Expression of ERas Oncogene in Gastric Carcinoma

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1 Expression of ERas Oncogene in Gastric Carcinoma RYOJI KAIZAKI 1, MASAKAZU YASHIRO 1,2, OSAMU SHINTO 1, KOICHI YASUDA 1, TARO MATSUZAKI 1, TETSUJI SAWADA 1 and KOSEI HIRAKAWA 1 1 Department of Surgical Oncology, and 2 Oncology Institute of Geriatrics and Medical Science, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka , Japan Abstract. Background: Embryonic stem cell expressed Ras (ERas) oncogene is associated with the tumorigenicity of embryonic stem cells. The aim of this study was to clarify the significance of ERas expression in clinical samples of gastric carcinomas. Materials and Methods: Three hundred and few tissues from gastric cancer patients were analyzed by immunohistochemical techniques using an anti-eras antibody. ERas mrna expression in 77 gastric carcinomas was examined by reverse-transcription polymerase chain reaction. Results: ERas expression was positive in 135 (44% ) of 304 gastric carcinomas. ERas-positive expression had a significant relationship with invasion depth (p<0.01), histological type (p<0.01), clinical stage (p=0.013) and curability (p=0.001). Prognosis of ERas-negative patients was significantly (p=0.029) poorer than that of ERas-positive patients, while ERas was not an independent prognostic factor. Expression of ERas mrna was found in 35 (45% ) out of 77 gastric cancer tissues. Conclusion: ERas oncogene is associated with the tumorigenic process of human gastric carcinomas. Embryonic stem cells (ES cells) are pluripotent cells derived from early mammalian embryos. ES cell expressed Ras (ERas) oncogene is a recently identified gene that supports the tumorigenic growth of ES cells (1-4). ERas protein contains amino acid residues identical to those present in active mutants of the conventional Ras oncogenes K-ras, N- ras and H-ras. The ERas product is a constitutively active Ras protein in the absence of mutation, while conventional ras oncogenes acquire activation of carcinogenesis by point mutation. The phosphatidylinositol-3-oh kinase cascade is important in the growth-promoting activity of ERas. Correspondence to: Masakazu Yashiro, MD, Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Asahi-machi, Abeno-ku, Osaka , Japan. Tel: , Fax: , m @med.osakacu.ac.jp Key Words: ERas, oncogene, gastric carcinoma, prognosis. ERas oncogene is expressed only in viviparity phase cells, but not in somatic normal cells because of epigenetic regulation in the somatic phase. Epigenetic regulation of tumor-associated genes is a common motif in many types of carcinomas (5), suggesting that ERas expression of somatic tumor cells might also be regulated by epigenetic modification. However, the expression of ERas oncogene of somatic malignant cells remains unclear. Although we previously reported that some cancer cell lines expressing ERas oncogene were regulated by epigenetic modification (6), there are no reports of ERas expression in clinical cancer samples. To clarify the significance of ERas oncogene in the malignant transformation of somatic cells, we examined the ERas expression of clinical gastric carcinoma in this study. Materials and Methods Clinical samples. A total of 381 patients who had undergone a resection of the primary tumor and were confirmed histologically to have sporadic gastric cancer were enrolled in this study. None of the patients had undergone pre-operative radiation and/or chemotherapy. The 304 of 381 primary tumor specimens were fixed in 10% formaldehyde solution and embedded in paraffin. Four micrometerthick sections were cut and mounted on glass slides for histological analysis. In addition, 77 fresh specimens of 381 primary gastric tumors were used for assessment of ERas mrna expression. The pathological diagnoses and classifications were made according to the Japanese Classification of Gastric Carcinoma by the Japanese Gastric Cancer Association (7). Antibodies and reagents. A mouse monoclonal antibody which recognizes ERas was produced in our laboratory as follows. Mice received primary immunizations in the foot pads with the ERas antigen combined with 15 mer peptide + Keyhole Limpet Hemocyanin (KLH), and received additional immunizations four times. Eight days after the final immunization, the spleens of the mice were excised. A single cell suspension of spleen cells was prepared. After the fusion entailing a splenocyte with a myeloma cell, hybridomas were selected by growth in a hypoxanthine-aminopterin-thymidine medium. Hybridoma cultures were screened to identify colonies secreting monoclonal antibodies specific to the target antigen via enzyme-linked immunosorbant assay in a 96-well plate. Hybridomas in positive cultures were cloned by limiting dilution. The monoclonal ERas antibody in the supernatant of hybridoma cultures was determined by Western blot using the ERas protein as an antigen and the supernatant /2009 $

2 of hybridoma cultures as the primary antibody. Human ERas protein was kindly provided by Professor Shinya Yamanaka (Department of Stem Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan). Cell lysates of mouse embryonic stem (ES) cells, 293T introduced with pmxs (Mock) or 293T introduced with pmxs encoding human ERas (HsERas) were separated by 12% SDS- PAGE and transferred to a PVDF membrane. Immunoblotting was performed with anti-eras antiserum. Monoclonal ERas antibody was produced from the hybridoma which showed ERas of 25 kda by Western blot. The hybridomas (10 7 cells) and 2,6,10,14- tetramethylpentadecane were injected into the intraperitoneal space of BALB/c mice. Ascites was amplified with the affigel protein A MAPS- II kit (BIO-RAD, Hercules, CA, USA), and the mouse monoclonal ERas antibody was completed. Western blot analysis showed that the mouse monoclonal ERas antibody detected ERas of 25 kda in ERastransfected cells, but not in mock-transfected cells (Figure 1A). Immunohistochemical determination of ERas. Normal rabbit serum, normal mouse immunoglobulin G, biotinylated rabbit anti-mouse immunoglobulin G, streptavidin-peroxidase reagent, and diaminobenzidine were purchased from Nichirei corporation (Tokyo, Japan). Immunohistochemical determination of ERas was carried out according to the manufacturer s instructions. In brief, the slides were deparaffinized in xylene and hydrated in decreasing concentrations of ethyl alcohol. The sections were deparaffinized and incubated with 3% hydrogen peroxide in methanol for 15 min to block endogenous peroxidase activity. The tissues were then heated for 10 min at 105 C by autoclaving in Target Retrieval Solution (Dako, Carpinteria, CA, USA). The sections were then washed in phosphate-buffered saline (PBS) and incubated in 10% normal rabbit serum for 10 min to reduce non-specific antibody binding. The specimens were incubated with ERas antibody overnight at 4 C, followed by two washes with PBS. The primary antibody used for the immunohistochemical detection of ERas was the mouse monoclonal ERas antibody. The sections were incubated with biotinylated rabbit anti-mouse immunoglobulin G for 10 min, followed by two washes with PBS. The slides were treated with streptavidin-peroxidase reagent for 5 min and washed with PBS twice. Finally, the slides were incubated in PBS diaminobenzidine and 1% (v/v) hydrogen peroxide for 60 s, counterstained with Mayer's hematoxylin, and mounted. The tumor cells were judged to be ERaspositive when unequivocal staining was seen in more than 20% of tumor cells. The slides were evaluated by two investigators (RK and MY) without any knowledge of the corresponding clinicopathological data, and when discordance was found, the cases were then re-evaluated together and a consensus was reached. Reverse-transcription polymerase chain reaction (RT-PCR). Fresh gastric cancer tissue was homogenised and mrna was extracted using Trizol (Invitrogen, Tokyo, Japan). After cdna was synthesized using oligo primer (Invitrogen), cdna was amplified by PCR for 35 cycles of denaturation at 94 C for 50 s, annealing at 59 C for 50 s, and extension at 72 C for 1 min. The following ERas primers were used: sense primer, 5 -ACCACGACCCCAC CATCCA-3 and antisense primer, 5 -GGACCAGCAGGGAA AAGGC-3. Statistical analysis. Comparative analyses of the data were performed using the Chi-square test or Fisher s exact test. Cox proportionalhazards regression was used to compute univariate and multivariate hazards ratios for the study parameters. A p-value of less than 0.05 was defined as being statistically significant. SPSS 10.0 software (SPSS Japan, Tokyo, Japan) was used for the analyses. Results The relationships between ERas protein expression and other clinicopathological parameters. ERas was mainly immunolocalized in the cytoplasm of cancer cells, while no ERas expression was found in normal gastric mucosa (Figure 1B). No difference of ERas staining was found between the infiltrative front and surface lesions in the same cases. In 304 gastric cancer patients, 135 (44% ) were positive for ERas staining. ERas-positive expression had a significant relationship with superficial flat tumor type (type 0; p<0.01), intestinal type (p<0.01), T1 (p<0.01), peritoneal dissemination (p=0.013), clinical stage I/II (p=0.013), and curability (p=0.001). In contrast, no significant relationship was found between ERas expression and lymph node disease, hepatic metastasis, peritoneal cytology, lymphatic invasion, or venous invasion (Table I). The prognosis of patients with ERas-negative tumors was significantly (p=0.029) worse than that of those with ERas-positive ones (Figure 2). In univariate analysis, ERas (p=0.040), morphological features (p<0.01), differentiation (p<0.01), depth of tumor invasion (p<0.01), peritoneal dissemination (p<0.01), lymph node disease (p<0.01), hepatic metastasis (p=0.003), cytology (p<0.01), lymphatic invasion (p<0.01), venous invasion (p=0.023), clinical stage (p<0.01) and curability (p<0.01) were significantly correlated with patient survival (Table II). In multivariate analysis, peritoneal cytology and tumor stage were statistically independent prognostic factors, but ERas was not (Table III). The relationships between ERas mrna expression and other clinicopathological parameters. Expression of ERas mrna was found in 35 (45% ) out of 77 gastric cancer tissues. ERas mrna tended to be more frequently expressed in patient with negative cytology (p=0.064) and early stage tumors (p=0.057) (Table IV). Discussion ERas is expressed only in viviparity phase cells, not in somatic cells (1-4). In this study, ERas expression was found in 135 (44% ) out of 304 somatic gastric carcinomas, while ERas expression was not found in normal gastric epithelium. In our preliminary study, RT-PCR analysis showed that ERas mrna was expressed in 35 (45% ) out of 77 gastric cancer lesions (data not shown). ERas-positive cases were significantly frequent in early-stage tumors. ERas is considered a member of the ras family including K-ras because they have a similar structure. Since K-ras mutation is found not only in colon cancer but also in colon adenomas, K-ras mutation has been considered to be associated with the early stage of tumorigenesis in colon cancer. Our findings suggested that not only K-ras but also ERas oncogene is associated with the 2190

3 Kaizaki et al: ERas Oncogene in Gastric Cancer Figure 1. A, Western blotting. The 25 kda band was recognized in ERas transfection protein by the anti-eras antibody, but not in mock-transfected cells (Mock). B, Hematoxylin and eosin (H&E) staining and immunohistochemical staining. A representative picture of ERas staining in gastric cancer was shown. ERas was found in the nucleus and cytoplasm of cancer cells, while no ERas expression was found in normal gastric epithelium. early stage of carcinogenesis in gastric epithelial cells. K-ras mutation has been reported to be correlated with the intestinal type of gastric cancer (8, 9). ERas was also frequently found in intestinal-type gastric carcinomas. These findings suggest that not only the K-ras signal but also the ERas signal might have an influence on differentiation. In gastric cancer, the K- ras mutation was reported to be found in 10% of cases (8), while ERas expression was found in 44%, suggesting that the Ras signal of ERas might play an important role in the proliferation of the intestinal type of gastric cancer compared to that of K-ras. The probability of overall survival in patients with ERas-positive tumors was significantly better than in those with ERas-negative ones. Multivariate analysis showed that ERas was not an independent prognostic factor for survival. These findings suggest that while the ERas gene may play an important role in tumorigenesis, it is not a predictive factor for survival. ERas was silent in somatic normal cells, but was frequently expressed in the early stage of malignant gastric tumors, although its expression was lower in advanced stages. Histone acetylation is reported to be one of the mechanisms responsible Figure 2. Survival curve. The overall survival of patients based on ERas expression. The survival curve shows the Kaplan-Meier overall survival curves in relation to the ERas expression level in the gastric carcinomas. The prognosis of all 304 patients with ERas-positive tumors was significantly (p=0.029) better than that of those with ERas-negative tumors. 2191

4 Table I. Correlations between ERas and clinicopathological features in 304 gastric cancer cases. Parameter ERas p-value Negative (n=169) Positive (n=135) Gender Male 106 (52.2% ) 97 (47.8% ) Female 63 (62.4% ) 38 (37.6% ) Morphologic type (46.2% ) 86 (53.8% ) < (38.1% ) 13 (61.9% ) 2 24 (60.0% ) 16 (40.0% ) 3 26 (65.0% ) 14 (35.0% ) 4 37 (86.0% ) 6 (14.0% ) Differentiated 46 (32.2% ) 97 (67.8% ) <0.01 Undifferentiated 121 (76.1% ) 38 (23.9% ) 1 74 (46.2% ) 86 (53.8% ) < (43.7% ) 18 (56.3% ) 3 77 (71.3% ) 31 (28.7% ) 4 4 (100.0% ) 0 (0.0% ) Negative 99 (52.4% ) 90 (47.6% ) Positive 70 (60.9% ) 45 (39.1% ) Negative 166 (55.5% ) 133 (44.5% ) Positive 3 (60.0% ) 2 (40.0% ) Negative 151 (53.5% ) 131 (46.5% ) Positive 18 (81.8% ) 4 (18.2% ) Peritoneal cytology Negative 134 (56.3% ) 104 (43.7% ) Positive 25 (71.4% ) 10 (28.6% ) Negative 99 (53.5% ) 86 (46.5% ) Positive 70 (58.8% ) 49 (41.2% ) Negative 140 (56.9% ) 106 (43.1% ) Positive 29 (50.0% ) 29 (50.0% ) Clinical stage I 80 (47.6% ) 88 (52.4% ) II 26 (61.9% ) 16 (38.1% ) III 30 (62.5% ) 18 (37.5% ) IV 33 (71.7% ) 13 (28.3% ) Curability ++ A 82 (47.1% ) 92 (52.9% ) B 52 (65.0% ) 28 (35.0% ) C 35 (74.5% ) 12 (25.5% ) +, Classification according to the General Rules for Gastric Cancer Study of the Japanese Research Society for Gastric Cancer. Type 0 is defined as a superficial, flat tumors; type 1 is defined as a polypoid tumor, sharply demarcated from the surrounding mucosa and usually attached on a wide base; type 2 as polypoid tumor with ulceration and with sharply demarcated margins; type 3 as ulcerated carcinoma with cancer infiltration into the surrounding wall; type 4 as diffusely infiltrating flat carcinoma in which ulceration is usually not a marked feature. ++, Curability A is defined as no residual disease with high probability of cure; curability B as no residual disease but not fulfilling criteria for Curability A ; curability C as definite residual disease. Significance level of difference was determined using Fisher s exact test or Chi-square test. Table II. Univariate analysis with respect to overall survival (n=304). Parameter Risk ratio 95% Confidence p-value interval ERas expression Negative vs. positive Morphologic feature Type 0 vs. type 1, 2, 3, and <0.01 Diffuse type vs. intestinal type <0.01 T1 vs. T2, T3, and T <0.01 Negative vs. positive <0.01 Negative vs. positive Negative vs. positive <0.01 Cytology Negative vs. positive <0.01 Negative vs. positive <0.01 Negative vs. positive Clinical Stage I and II vs. III and IV <0.01 Curability A vs. B and C <0.01 Table III. Multivariate analysis with respect to overall survival (n=304). Parameter Risk ratio 95% Confidence p-value interval ERas expression Negative vs. positive Morphologic feature Type 0 vs. type 1, 2, 3, and Diffuse type vs. intestinal type T1 vs. T2, T3, and T Negative vs. positive Negative vs. positive Negative vs. positive Cytology Negative vs. positive Negative vs. positive Negative vs. positive Clinical Stage I and II vs. III and IV Curability A vs. B and C

5 Kaizaki et al: ERas Oncogene in Gastric Cancer Table IV. Correlation between ERas (mrna) and clinicopathological features in 77 gastric cancer cases. Parameter ERas mrna p-value Negative (n=42) Positive (n=35) Gender Male 28 (50.9% ) 27 (49.1% ) Female 14 (63.6% ) 8 (36.4% ) Morphological type (52.9% ) 8 (47.1% ) (40.0% ) 3 (60.0% ) 2 5 (38.5% ) 8 (61.5% ) 3 18 (66.7% ) 9 (33.3% ) 4 5 (50.0% ) 5 (50.0% ) 5 2 (50.0% ) 2 (50.0% ) Differentiated 18 (52.9% ) 16 (47.1% ) Undifferentiated 23 (54.8% ) 19 (45.2% ) 1 9 (47.4% ) 10 (52.6% ) (53.3% ) 7 (46.7% ) 3 21 (53.8% ) 18 (46.2% ) 4 4 (100.0% ) 0 (0.0% ) Negative 17 (54.8% ) 14 (45.2% ) Positive 23 (52.3% ) 21 (47.7% ) Negative 41 (53.9% ) 35 (46.1% ) Positive 1 (100.0% ) 0 (0.0% ) Negative 32 (50.8% ) 31 (49.2% ) Positive 10 (71.4% ) 4 (28.6% ) Peritoneal cytology Negative 21 (43.8% ) 27 (56.3% ) Positive 14 (70.0% ) 6 (30.0% ) Negative 9 (52.9% ) 8 (47.1% ) Positive 32 (54.2% ) 27 (45.8% ) Negative 23 (50.0% ) 23 (50.0% ) Positive 18 (60.0% ) 12 (40.0% ) Clinical stage I 13 (48.1% ) 14 (51.9% ) II 4 (66.7% ) 2 (33.3% ) III 5 (31.3% ) 11 (68.8% ) IV 20 (71.4% ) 8 (28.6% ) +, Classification according to the General Rules for Gastric Cancer Study of the Japanese Research Society for Gastric Cancer. Type 0 is defined as a superficial, flat tumors; type 1 as a polypoid tumor, sharply demarcated from the surrounding mucosa and usually attached on a wide base; type 2 as polypoid tumor with ulceration and with sharply demarcated margins; type 3 as ulcerated carcinoma with cancer infiltration into the surrounding wall; type 4 as diffusely infiltrating flat carcinoma in which ulceration is usually not a marked feature; type 5 as non-classifiable carcinomas that cannot be classified into any of the above types. Significance level of difference was determined using Fisher s exact test or Chi-square test. for the epigenetic regulation performed by on-off reversible systems in the epigenetic transcriptional silencing of the ERas oncogene (6). The epigenetic transcription might be associated with the regulation of ERas expression in the process of tumorigenesis in human gastric cancer. In conclusion, ERas oncogene was frequently expressed in the early stage of gastric cancer, while no ERas expression was found in normal epithelium. ERas oncogene might be closely associated with the tumorigenesis of human gastric carcinomas. Acknowledgements We thank professor Shinya Yamanaka (Department of Stem Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan), Midori Komatsu (Osaka City University Graduate School of Medicine), and Masako Shinkawa (Osaka City University Graduate School of Medicine) for helpful advice. This study was partially founded by Japan-China Sasagawa Medical Scholarship, by Grants-in Aid for Scientific Research (Nos , , and ) from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a JSGE Grant-in Aid for Scientific Research, by a Grant-in Aid for Kobayashi Foundation for Innovative Cancer Chemotherapy, by a Grant-in Aid for the Sagawa Foundation for Cancer Research, and by a Grant-in Aid for the Osaka Medical Research Foundation for Incurable Diseases. References 1 Takahashi K, Mitsui K and Yamanaka S: Role of ERas in promoting tumour-like properties in mouse embryonic stem cells. Nature 423: , Takahashi K, Murakami M and Yamanaka S: Role of the phosphoinositide 3-kinase pathway in mouse embryonic stem (ES) cells. Biochem Soc Trans 33: , Takahashi K, Nakagawa M, Young SG and Yamanaka S: Differential membrane localization of ERas and Rheb, two Rasrelated proteins involved in the phosphatidylinositol 3- kinase/mtor pathway. J Biol Chem 280: , Kameda T and Thomson JA: Human ERas gene has an upstream premature polyadenylation signal that results in a truncated, noncoding transcript. Stem Cells 23: , Fang JY and Lu YY: Effects of histone acetylation and DNA methylation on p21( WAF1) regulation. World J Gastroenterol 8: , Yasuda K, Yashiro M, Sawada T, Ohira M and Hirakawa K: ERas oncogene expression and epigenetic regulation by histone acetylation in human cancer cells. Anticancer Res 27: , Japanese Gastric Cancer A. Japanese Classification of Gastric Carcinoma - 2nd English Edition. Gastric Cancer 1: 10-24, Yashiro M, Nishioka N and Hirakawa K: K-ras mutation influences macroscopic features of gastric carcinoma. J Surg Res 124: 74-78, Akkiprik M, Celikel CA, Dusunceli F, Sonmez O, Gulluoglu BM, Sav A and Ozer A: Relationship between overexpression of ras p21 oncoprotein and K-ras codon 12 and 13 mutations in Turkish colorectal cancer patients. Turk J Gastroenterol 19: 22-27, Received February 24, 2009 Revised April 14, 2009 Accepted April 27,

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