Peptidase Inhibitor 15 As A Novel Blood Diagnostic Marker For Cholangiocarcinoma

Objectives Cholangiocarcinoma(CCA)lacks specific diagnostic markers.In this study,we screened the differentially expressed genes encoding secretory protein in cholangiocarcinoma tissues and matched normal tissues to search for a novel blood diagnostic marker for CCA,providing a new approach for the diagnosis of patients with CCA.Methods Starting with the analysis of gene expression profiles in tumor tissues and matched normal tissues from cases with CCA and hepatocellular carcinoma(HCC),and combining with the CCA and HCC m RNA expression data accessed by RNA-seq from TCGA database,we screened the differentially expressed genes encoding secretory protein and identified peptidase inhibitor 15(PI15)was a potential diagnostic marker for CCA.The expression of PI15,other tumor markers consisting of AFP,CEA,CA125,PSA and GH was detected by PCR in CCA,HCC and normal liver tissues.ELISA assessed plasma PI15 levels in CCA(n=61),HCC(n=72),benign liver disease(n=28),chronic hepatitis B patients(n=45)and healthy individuals(n=45),the serum carbohydrate antigen 19–9(CA19–9)levels in these patients were detected by electrochemiluminescence.ROC curve and multivariate logistic regression model were used to access the diagnostic value of PI15,CA19-9 and PI15 combined with CA19–9.Results(1)The positive rate of PI15 expression was 70% in CCA and only 9.1% in HCC.PI15 was not detected in normal liver tissues.(2)The positive rate of PI15 expression was higher than that of other tumor markers.(3)Plasma PI15 levels were significantly upregulated in CCA patients,which were significantly higher than that of HCC patients,benign liver disease patients,chronic hepatitis B patients and healthy individuals.(4)Plasma PI15 levels in CCA patients were obviously reduced(P<0.01)after surgery.No statistically significant differences of plasma PI15 levels were observed in HCC and benign liver disease patients before and after surgery.(5)The AUC of plasma PI15 for discriminating between CCA and HCC was 0.735.Furthermore,with a specificity of 94.44%,the combination of CA19-9(>98.5 U/m L)and PI15(>13 ng/m L)yielded a sensitivity of 80.39% for CCA and HCC.Conclusions(1)The expression of PI15 was highly upregulated with specificity in CCA.(2)Plasma PI15 had the potential to act as diagnostic marker for CCA.(3)Plasma PI15 exhibited promise as detection index for the follow-up of CCA patients.(4)The combination of plasma PI15 and serum CA19-9 exhibited superior diagnostic performance for CCA patients.