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Overexpression of CIAPIN1 Inhibited Pancreatic Cancer Cell Proliferation and Was Associated with Good Prognosis in Pancreatic Cancer

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Overexpression of CIAPIN1 Inhibited Pancreatic Cancer Cell Proliferation and Was Associated with Good Prognosis in Pancreatic Cancer Cancer Gene Therapy (2012) 19, 538 -- 544 & 2012 Nature America, Inc. All rights reserved 0929-1903/12 www.nature.com/cgt ORIGINAL ARTICLE Overexpression of CIAPIN1 inhibited pancreatic cancer cell proliferation and was associated with good prognosis in pancreatic cancer X Chen1,4,XLi1,4, J Chen2,4, P Zheng1, S Huang3 and X Ouyang1 Cytokine-induced antiapoptotic molecule (CIAPIN1), a newly identified apoptosis inhibitor, has been found to participate in the process of proliferation and tumorigenicity for several cancers. The aim of this study was to evaluate the prognostic value of CIAPIN1 in pancreatic cancer and to probe its function in pancreatic carcinogenesis. We found that CIAPIN1 protein was absent or reduced in pancreatic cancer cell lines. There was also a loss or decrease in CIAPIN1 expression in 118 cases of pancreatic cancer tissues as compared with that in 82 cases of normal pancreatic tissues. In a Cox proportional hazards model, CIAPIN1 expression independently predicted better survival (Po0.0001). Adenoviral-mediated restoration of CIAPIN1 expression greatly repressed the proliferation of pancreatic cancer cell in vitro and suppressed the tumorigenicity of pancreatic cancer cell in Balb/ c nude mice. Our data also revealed that inhibition of pancreatic cancer cells proliferation by enforcing CIAPIN1 expression at least partly through delaying cell cycle progression and inducing cell apoptosis. In summary, our work revealed a novel function of CIAPIN1, which might possibly be used as an independent prognostic factor and a potential therapeutic target for pancreatic cancer. Cancer Gene Therapy (2012) 19, 538--544; doi:10.1038/cgt.2012.28; published online 8 June 2012 Keywords: apoptosis; cell cycle; CIAPIN1; pancreatic cancer; proliferation INTRODUCTION cancer,7--15 which strongly suggested that CIAPIN1 might be an Pancreatic cancer is highly lethal, with median survival time of o6 important protein involving in tumorigenicity and carcinogenesis. months and an overall 5-year survival rate of all patients is o1%.1 Although the expression level of CIAPIN1 has been found to It is the fourth leading cause of cancer-related deaths in the relate to many different solid tumors and may act as an oncogene United States.2 According to the American Cancer Society, there or tumor suppressor in different tumor types, the role of are an estimated 42 470 new cases and 35 240 deaths from CIAPIN1 in pancreatic cancer is still unknown. To further elucidate pancreatic cancer in the United States in 2009.3 The lethal nature the biological role of CIAPIN1, in the present study, we of pancreatic cancer is due to late detection, fast growth, a feature examined the expression of CIAPIN1 in tumor tissue specimens to invade and metastasize, and resistance to traditional therapy. It obtained from patients with resected pancreatic cancer and its is a critical need for finding a new molecularly targeted therapy effect on the patients’ survival duration. We found that loss of that can improve the outcome for those diagnosed with CIAPIN1 expression directly correlated with decreased survival. pancreatic cancer. We also found that restoration of CIAPIN1 expression inhibited the CIAPIN1 (cytokine-induced antiapoptosis inhibitor 1) is a newly growth and proliferation of human pancreatic cancer cells identified apoptosis inhibitor with no homology to apoptosis in vitro and in vivo. Induction of cell cycle arrest and apoptosis regulatory molecules of the Bcl-2 family, caspase family or signal was at least in part responsible for the antitumor activity transduction molecules, is proven to be a mediator of the RAS of CIAPIN1. In conclusion, our experiment results indicated that signaling pathway and has an important role in fetal liver CIAPIN1 was a significant prognostic factor, and targeting of hematopoiesis.4 Additionally, CIAPIN1 protects Ba/F3 cells CIAPIN1 was a potential treatment modality for human pancreatic against etoposide, gamma radiation and stauroporine in vitro.4 cancer. In addition, our previous study confirmed that CIAPIN1 was upregulated in several multidrug resistance cancer cell lines and might have a role in mediating multidrug resistance of cancer MATERIALS AND METHODS cells.5,6 Furthermore, CIAPIN1 expression was correlated with Ethics statement malignant phenotype of several cancers such as gastric cancer, This study was performed in accordance with the principles embodied in liver cancer, esophagus cancer, lung cancer, lymphoma and kidney the Declaration of Helsinki. All experimental procedures were approved by 1Department of Medicine Oncology, Fuzhou General Hospital of Nanjing Military Command, Fuzhou, Fujian, China; 2Department of Statistic, Fuzhou General Hospital of Nanjing Military Command, Fuzhou, Fujian, China and 3Department of General Surgery, Fuzhou General Hospital of Nanjing Military Command, Fuzhou, Fujian, China. Correspondence: Professor X Ouyang or Dr X Chen, Department of Medicine Oncology, Fuzhou General Hospital of Nanjing Military Command, 156 Xierhuan Northern Road, Fuzhou, 350025, Fujian Province, PR China. E-mail: [email protected] (XO) or [email protected] (XC) 4These authors contributed equally to this work. Received 13 February 2012; revised 24 April 2012; accepted 26 April 2012; published online 8 June 2012 Prognostic value of CIAPIN1 in pancreatic cancer X Chen et al 539 the Institutional Review Board of The Fuzhou General Hospital and the 1 : 300 dilution) at 4 1C overnight. The sections were then sequentially Fourth Military Medical University. Written informed consent was obtained incubated with a biotinylated anti-mouse immunoglobulin solution for for all patient samples. Animal experiments were performed with the 20 min followed by peroxidase-labeled streptavidin for 20 min. The approval of the Institutional Committee of The Fuzhou General Hospital reaction products were visualized using 3,3-diaminobenzidine as a and the Fourth Military Medical University for Animal Research and in chromogen followed by nuclear counterstaining with hematoxylin. conformity with national guidelines for the care and use of laboratory Two independent investigators scored the sections without any animals. knowledge of the clinical features of each case. An average value of two independent scores was presented in the present study. Depending on the Clinical samples percentage of positive cells and staining intensity, CIAPIN1 staining positivity was classified into three groups: negative, weak positive and Paraffin-embedded tumor samples from 118 patients aged 41 to 80 years strong positive, as described previously.17 (mean 61, median 60; 53 women, 65 men), who were diagnosed with a primary ductal adenocarcinoma of the pancreas and who underwent tumor resection at the Department of Surgery in Fuzhou General Hospital, Cell culture and adenovirus infection Fuzhou, China and Department of General Gastrointestinal Surgery in Human pancreatic cancer cell lines PANC-1, BxPC-3, ASPC-1 (purchased Xijing Hospital, Xi’an, China between 2002 and 2007. The median follow-up from American Type Culture Collection, Manassas, VA, USA), PC-2 and PC-3 period was 17.8 months. No neo-adjuvant radio- or chemotherapy was (established in Peking Union Medical College)18 were maintained in our applied before surgical resection to any patient. Table 1 showed the details laboratory and cultivated in RPMI 1640 (Life Technologies, Grand Island, of the patients’ characteristics and CIAPIN1 expression situation. Histologic NY, USA) supplemented with 10% heat-inactivated FCS, penicillin grading and staging of all tumors were performed according to the TNM (100 units ml--1), and streptomycin (100 Ag ml--1) in a CO2 incubator (Forma classification system of the International Union against Cancer.16 Scientific, Waltham, MA, USA). Preparation and construction of Ad-CIAPIN1 and Ad-EGFP vector, and adenovirus titration were carried out as 18 Immunohistochemistry previously described Chen et al. PC-2 and PANC-1 pancreatic cancer- derived cell lines were transduced using standard techniques as previously Sections were cut at 4-mm thickness from paraffin-embedded material, reported.19 deparaffinized in xylene and rehydrated through a graded ethanol series. Endogenous peroxidase activity was blocked by incubating with 3% hydrogen peroxide in methanol for 30 min. Antigen retrieval was achieved Cell proliferation assay by microwaving the sections in citrate buffer at pH 6.0. Each section was The proliferation of cells was evaluated as previously described.20 By the exposed to 10% nonimmunized rabbit serum for 10 min to block conversion of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide nonspecific binding of the antibodies, followed by incubation with a (MTT; Sigma Chemical, St Louis, MO) into water-insoluble formazan by mouse anti-CIAPIN1 monoclonal antibody (produced in our laboratory viable cells. Three thousand cells in 200 ml of medium were plated in Table 1. Clinicopathological associations of CIAPIN1 expression in patients with pancreatic cancer Characteristic Total (n ¼ 118) CIAPIN1 staining w2 Value (or F-value) P-value Negative (n ¼ 62) Weak (n ¼ 38) Strong (n ¼ 18) Gender Female 53 (100.0%) 30 (56.6%) 16 (30.2%) 7 (13.2%) 0.6875 0.7091 Male 65 (100.0%) 32 (49.2%) 22 (33.8%) 11 (17.0%) Age, years 59.68±8.08 62.50±7.21 61.94±4.60 1.9200 0.1501 Depth of invasion T2 17 (100.0%) 7 (41.2%) 5 (29.4%) 5 (29.4%) 20.7401 0.0004 T3 37 (100.0%) 21 (56.8%) 5 (13.5%) 11 (29.7%) T4 64 (100.0%) 34 (53.1%) 28 (43.8%) 2 (3.1%) Lymph node status N0 28 (100.0%)
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