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A1-Antitrypsin Precursor in Gastric Juice Is a Novel Biomarker For

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A1-Antitrypsin Precursor in Gastric Juice Is a Novel Biomarker For Imaging, Diagnosis, Prognosis A1-Antitrypsin Precursor in Gastric Juice Is a Novel Biomarker for Gastric Cancer and Ulcer Ping-I Hsu,1Chung-Hsuan Chen,2 Chieu-Shia Hsieh,1Wei-Chao Chang,2 Kwok-Hung Lai,1Gin-Ho Lo,1 Ping-Ning Hsu,3 Feng-Woei Tsay,1Yu-Shan Chen,1Michael Hsiao, 2 Hui-Chun Chen,4 and Pei-Jung Lu5 Abstract Purpose:Tosearch for novel disease-specific markers in gastric juice by investigating the protein concentrations and components in gastric juice from patients with various gastroduodenal diseases. Experimental Design: Protein concentrations and pH values in fasting gastric juice were examined in 120 healthy subjects and 39 gastric ulcer, 38 duodenal ulcer, and 31gastric cancer patients. The protein components in gastric juice were studied by two-dimensional PAGE and mass spectrometric analysis. Results: Protein concentrations in gastric juice of patients with gastric ulcers and gastric cancer were significantly higher than those in healthy subjects (1.06 and 2.61 mg/mL versus 0.48 mg/mL; P =0.001andP < 0.001, respectively), and duodenal ulcer patients had lower gas- tric juice protein concentrations compared with healthy subjects (0.26 versus 0.48 mg/mL; P < 0.05). Gastric hypoacidity and advanced age were independent factors affecting the protein concentrations in gastric juice with odds ratios of 32.9 (95% confidence interval, 11.8-90.9) and 3.2 (95% confidence interval, 1.3-8.3), respectively. Each electrophoresis images of gastric juice could be classified into one of three patterns: basic band, specific band, or nonspecific band.The frequencies of specific band pattern in healthy subjects, gastric ulcer, duodenal ulcer, and gastric cancer patients were 6%, 42%, 6%, and 93%, respectively. Proteomic analysis revealed that a1-antitrypsin precursor was the principal peptide in the specific band. Conclusions: a1-antitrypsin precursor in gastric juice is a novel biomarker for gastric cancer and ulcer. A noninvasive method to obtain gastric juice followed by proteomic analysis may serve as a new tool to screen for gastric malignancies. Gastric juice contains numerous compounds, including hydro- odenal reflux, inflammatory mediators or blood from damaged chloric acid, pepsin, lipase, mucin, intrinsic factor, peptides, gastric walls, and oncoproteins from gastric cancers (2). nucleic acids, and electrolytes (1). Additionally, it may contain Recently, Kasirga et al. (3) showed that gastric juice leukotriene salivary constituents due to swallowing, bile due to gastrodu- levels were significantly higher in patients with Helicobacter pylori infection than in subjects without infection. Marcinkiewicz et al. (4) also showed that gastric mucosa damage by 1 Authors’ Affiliations: Division of Gastroenterology, Department of Internal naproxen sodium resulted in profound changes of gastric Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University; 2Genomics Research Center, Academic Sinica; 3Department Graduate Institute of mucosal barrier, and analysis of residual compounds in gastric Immunology, National Taiwan University,Taipei, Taiwan; 4Department of Radiation juice adequately reflected these changes. Aforementioned fin- Oncology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, College of dings suggest that analysis of protein components of gastric 5 Medicine, Chang Gung University; and Department of Medical Education and juice allows accurate discrimination between normal and Research, Kaohsiung Veterans General Hospital and National Sun Yat-Sen University, Kaohsiung, Taiwan diseased gastric mucosa. Received 6/12/06; revised 11/20/06; accepted 12/5/06. Recently, a small gelatin capsule containing a pierced plastic Grant support: Research Foundation of Kaohsiung Veterans General Hospital cover surrounding a piece of absorbent paper was developed to grant VGHKS94-46 and National Science Council,Taiwan, grant NSC-93-2314-B- obtain gastric juice (5). Additionally, a noninvasive string test 075B-013. The costs of publication of this article were defrayed in part by the payment of page has also been reported useful to obtain gastric juice samples for charges. This article must therefore be hereby marked advertisement in accordance the diagnosis of H. pylori infection (6). This technique with 18 U.S.C. Section 1734 solely to indicate this fact. facilitates epidemiologic studies for assessing H. pylori status Note: P-I. Hsu and C-H. Chen contributed equally to this work. in asymptomatic subjects without the need for endoscopy (7). Institutions and Departments where the work was accomplished: Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan and To date, there are no reliable noninvasive methods to screen for Genomics Research Center, Academic Sinica,Taipei,Taiwan. or diagnose gastric cancer. Recent studies indicate that the Requests for reprints: Pei-Jung Lu, Department of Medical Education and development of intestinal-type gastric adenocarcinoma is a Research, Kaohsiung Veterans General Hospital, 386 Ta Chung 1st Road, multistep event progressing from superficial gastritis, atrophic Kaohsiung 813,Taiwan, Republicof China Phone: 886-7-3422121, ext. 1513; gastritis, intestinal metaplasia, and dysplasia to malignancy Fax: 886-7-3468237; E-mail: [email protected]. F 2007 American Association for Cancer Research. through cumulative multiple genetic changes (8–11). With doi:10.1158/1078-0432.CCR-06-1404 regard to diffuse-type gastric cancer, the loss of adhesion Clin Cancer Res 2007;13(3) February1,2007 876 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2007 American Association for Cancer Research. Biomarkers in Gastric Juice molecules, such as E-cadherin, catenin, and Annexin 7, was (50 Ag per gel) was analyzed by two-dimensional electrophoresis, and involved in the carcinogenesis (12–14). Because the sequential protein spots of interest were identified by mass spectrometric (MS) changes of gastric foveolar epithelium and glands during the analysis. course of cancer development can lead to alterations of the Two-dimensional electrophoresis analysis of protein components in gastric juice. The two-dimensional gel electrophoresis was carried out components in gastric juices, proteomic studies of gastric juice as described previously (22, 23). The first dimension of gel separation hold a great potential to discover novel tumor-specific markers was done using commercially available dedicated apparatus: IPGphor for screening of gastrointestinal malignancies. (Amersham Pharmacia Biotech, Uppsala, Sweden). A sample contain- This study was therefore designed to investigate the protein ing 50 Ag of protein was precipitated with acetone (1:2, v/v) for 2 h at concentrations and components in gastric juice of patients with À20jC, and the mixture was centrifuged at 10,000  g for 10 min at various gastroduodenal diseases in an aim to discover novel 4jC. The pellet was mixed with rehydration solution (9 mol/L urea, disease-specific markers in gastric juice. 35 mmol/L Tris, 42 mmol/L DTT, 2% CHAPS, 0.66% SDS, 2% IPG buffer, and trace bromphenol blue) and applied to 11-cm nonlinear pH 4-7 immobilized pH gradient strips (Immobiline DryStrip, Materials and Methods Amersham Pharmacia Biotech) for overnight rehydration at 30 V. Proteins were focused sequentially for 1 h at 200 V, 1 h at 500 V, and Subjects. One hundred and twenty consecutive healthy subjects, 1 h at 1,000 V, then a gradient was applied from 1,000 to 8,000 V for 39 patients with gastric ulcer, 38 patients with duodenal ulcer, and 30 min, and focusing was continued at 8,000 V for 8.5 h to give a total 31 patients with gastric cancer participated in the study. The healthy of 70 kVh on an IPGphor. For the second dimension, the IPG strips subjects that were recruited from our health examination clinics had no were equilibrated for 12min in 50 mmol/L Tris-HCl (pH 8.8), 6 mol/L clinical history of gastrointestinal diseases, and their endoscopic urea, 30% glycerol, 1% DTT, and bromphenol blue and then for 12min findings were normal or showed only mild gastritis. The diagnosis of in 50 mmol/L Tris-HCl (pH 8.8), 6 mol/L urea, 30% glycerol, l.2% SDS, gastric ulcer and duodenal ulcer was confirmed by endoscopic 2% iodoacetamide, and bromphenol blue. The strips were applied on   examination (15). The patient exclusion criteria included (a) the use top of a 15% gradient acrylamide gel slab (190 140 1 mm), and of proton pump inhibitors, H2-receptor antagonists, or nonsteroidal electrophoresis was done overnight. The gels were stained with silver anti-inflammatory drugs within 4 weeks before the study; (b) nitrate (22). Protein patterns in the gels were recorded as digitalized coexistence of two kinds of gastroduodenal lesions; (c) presence of images using a high-resolution scanner (GS-710 Calibrated Imaging upper gastroduodenal bleeding; and (d) coexistence of severe systemic Densitometer, Bio-Rad, Hercules, CA). Gel image matching was done diseases. Gastric cancer was confirmed by histology and classified as with PDQuest software (Bio-Rad). intestinal (n = 19), diffuse (n = 9), and mixed (n = 3) according to the In-gel tryptic digestion. The in-gel tryptic digestion was done as Lauren’s classification (16). The extent of tumor invasion in gastric described previously (24). Briefly, the gel pieces were digested with cancer patients undergoing surgery (n = 27) was further divided into porcine trypsin (Promega, Madison, WI) and the peptides were early or advanced gastric
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