Expression And Clinical Prognosis Of Interferon Alpha-inducible Protein 27 In Pancreatic Cancer

Background:Pancreatic cancer（PC）is a malignant and aggressive tumor of the gastrointestinal tract.Most patients in the early stages lack typical clinical symptoms and are therefore difficult to detect,resulting in at least 50% of patients being lost to surgery by the time they are diagnosed.Therefore,current emphasis in the diagnosis and treatment of PC is on searching for early diagnosis markers and new targets for treatment.ISG12 is a group of type I interferon highly inducible genes distinguished by the possession of a strongly constrained 80 amino acid structural region,called the ISG12 motif.The human ISG12 family members include IFI27（ISG12a）,IFI27L2（ISG12b）,IFI27L1（ISG12c）,and IFI6（ISG6-16）.IFI27,the most prominent gene in the ISG12 family,is strongly induced by type I interferon and is involved in the innate immunity and cell proliferation of the organism.Recent experimental data show that IFI27 is a small-molecule hydrophobic protein,mainly enriched in mitochondria,which makes cells sensitive to apoptosis through the destabilizing effect of the mitochondrial membrane.Its expression was also relevant to the progression of a variety of tumors,including ovarian,liver,bile duct,breast,and squamous cell skin cancers.Objective:To investigate the expression of IFI27 in pancreatic cancer and corresponding paraneoplastic non-tumor tissues,as well as the correlation with the clinicopathological characteristics and prognosis of pancreatic cancer patients,and to explore the possible mechanisms of IFI27’s role in pancreatic cancer.Methods:1.The expression of gene IFI27 in various types of human tumor tissues（including PAAD）and pancreatic cancer cell lines was analyzed by bioinformatics methods in GEPIA database,CCLE database,and TCGA database to investigate the association between IFI27 expression levels and overall survival（OS）of pancreatic cancer patients;2.Possible involvement of IFI27 in the regulation of signaling pathways in pancreatic cancer by ss GSEA and co-expression gene enrichment analysis（GO and KEGG）;3.Differential expression of IFI27 mRNA between pancreatic cancer cell lines and human normal pancreatic epithelial cells detected by q-PCR;4.IHC was conducted to explore the existence of differences in the expression of IFI27 protein in pancreatic cancer tissues and paracancerous tissues,and to analyze the association between positive IFI27 protein expression and clinicopathologic parameters and prognosis of PC patients.Results:1.The bioinformatics analysis revealed that IFI27 was highly expressed in pancreatic cancer tissues compared to normal pancreatic tissues and was associated with poor prognosis of patients with median survival of 24 and 15.6 months,respectively（HR:2.065,95% CI:1.358-3.138,P=0.00069）.GO enrichment analysis of IFI27 co-expressed genes enriched in biological processes such as type I interferon signaling pathway,cellular response to type I interferon,negative regulation of viral processes,response to viruses;KEGG pathway analysis of IFI27 co-expressed genes enriched in human papillomavirus infection,hepatitis C,ECM-receptor interaction,influenza A,estrogen signaling pathway,IL-17 signaling pathway.ss GSEA combined with Spearman correlation analysis revealed that IFI27 was strongly associated with two biological processes,namely P53 signaling pathway and tumor proliferation,in pancreatic cancer.TIMER database shows substantial positive association of IFI27 with MKI67 and PCNA,genes encoding molecular markers of tumor proliferation,in pancreatic cancer.2.The q-PCR results showed that IFI27 mRNA was expressed at high levels in human pancreatic cancer cell lines SW1990 and CFPAC-1,and at low levels in PANC-1,As PC-1 and normal pancreatic epithelial cells HPNE,and the differences between SW1990 and CFPAC-1 were statistically significant when compared with HPNE,respectively（P<0.05）.3.IHC showed that IFI27 was significantly more positive in pancreatic cancer tissues than in paraneoplastic non-tumor tissues（P<0.05）.IFI27 expression correlated with TNM stage and Ki-67 positivity index >20%（P<0.05）in pancreatic cancer patients,but not with patient gender,preoperative CA19-9 level,site of tumorigenesis,vascular invasion,and nerve invasion were not related.OS of pancreatic cancer patients was correlated with positive IFI27 expression,gender,TNM stage,T stage,presence of lymphatic metastasis,presence of distant metastasis,and presence of vascular invasion（P<0.05）were correlated with other clinicopathological parameters.Multifactorial analysis showed that gender,TNM stage,T stage,presence of distant metastases,and IFI27 protein expression could be independent prognostic factors for pancreatic cancer patients（P < 0.05）,where the risk of death was 1.783 times higher in patients with high IFI27 expression than in those with low expression.conclusion:1.IFI27 was highly expressed in pancreatic tissues,and its expression correlated with TNM stage and Ki-67 positivity index >20% in PC.2.Patients in the group with high IFI27 expression had a poorer prognosis,and positive IFI27 expression was an independent prognostic indicator for PC.3.IFI27 promises to be a novel marker for assessing the prognosis of pancreatic cancer.