Expression Of ABCG2,HIF-1 In Pancreatic Cancer And The Correlation With Clinical Significance

IntroductionMultidrug resistance (MDR) is one of the main reasons resulting in failure of chemotherapy in patients with pancreatic cancer. The over expression of multldruge resistance associated protein (MRP) play a more important role in MDR, and MRP includes pancreatic cancer resistant protein (BCRP/ABCG2), which discovered lately. Camptothecin is substrates of ABCG2, and properly camptothecin was commonly used in treatment of pancreatic cancer. It is important to investigate the expression of ABCG2 in pancreatic cancer and the correlation with camptothecin.Hypoxia inducible factor-1 (HIF-1) has tightly correlation with MDR, and can up-regulate the expression of P-gp and MRP, which have binding motifs of HIF-1 in promoter field as well as ABCG2. We think that HIF-1 also can up-regulate the expression of ABCG2.In this study, we detected the expression of ABCG2 and HIF-1 using immunohistochemical SP methods to investigate the relationship between them, as well as the correlate with clinicopathological parameters.Methods1. Patients90 pancreatic patients underwent completely resected which were enrolled from the ShengJing Hospital, China Medical University (CMU). None of them underwent chemotherapy or radiotherapy before operation. And 67 cases were pancreatic cancer with median age of 64 years. Among of them there were 57 ductal carcinoma cases (18 high differentiation cases; 17 middle differentiation cases and 22 low differentiation cases) and 10 cystadenocarcinoma. The range of 11 benign tumors and 12 normal tissues was 38-70 years.2. Materials The monoclonal antibodies against HIF-1 and DAB substrate solution were purchased from Bejing Zhongshan Biotechology, Inc; the monoclonal antibodies against ABCG2 were purchased from American Santa Biotechology, Inc; The SP immunohistochemical kits were purchased from Fuzhou Maixin Biotechology, Inc.3. MethodsImmunohistochemical staining SP method was performed. All slides were treated with 0.01mol/L citric acid buffer (PH=6.0) and recovered the antigen activity by autoclave.4. AssessmentOutcome definition of ABCG2 were stained palm yellow particle in cell cytosol and nucleus, positive cells≤10% as negative,>10% as positive, at high magnification(×400). Outcome definition of HIF-1 were stained palm yellow particle in cytosol or nucleus, positive cells<10% as negative,>10% as positive, at high magnification(×400).5. Statistical analysisStatistical methodsχ2 test, spearman rank correlation test were performed by SPSS software version 16.0.Results1. Expression of ABCG2 and HIF-1 in pancreatic cancer patientsPositive expression of ABCG2 and HIF-1 in 67 cases was 62.7% and 55.2% respectively, however, was negative in 23 cases normal pancreas tissue and benign tumors.2. The relationship between expression of ABCG2 and HIF-1 and clinicopathologic parameters in pancreatic cancer patients.Expression of ABCG2 was positive correlated with tumor size (r=0.284, p=0.020) and tumor differentiation (r=0.326, p=0.013), but not correlated with lymph node metastasis(r=0.209, p=0.090) and clinical stage (r=0.114, p=0.399). Expression of HIF-1 was positive correlated with tumor size (r=0.304, p=0.013) and clinical stage (r=0.296, p=0.025), but not correlated with lymph node metastasis(r=0.022, p=0.858) and tumor differentiation (r=0.326, p=0.013). 3. The relationship between expressions of ABCG2 and HIF-1.In 67 pancreatic cancers there were 37 positive cases of HIF-1, in which 28 positive cases of ABCG2; there were 30 negative cases of HIF-1, in which 14 positive cases of ABCG2. Expression of ABCG2 was positive correlated with HIF-1 (r=0.298, p=0.015).Conclusion1. Expression of ABCG2 and HIF-1 were bad predictors for patients received.2. Expression of ABCG2 was positive correlated with expression of HIF-1.3.Detection of ABCG2/HIF-1 in pancreatic cancer tissues might be significant in prognosis prediction and sensitivity to camptothecin.