| Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease, and its prevalence has been increasing in recent years. However, the early lesions of pancreas can not be effectively detected by images due to its retroperitoneal location. Moreover, there are currently no ideal markers with sufficient sensitivity and specificity to detect this kind of cancer early enough to effect cures. Recently, pathologists raised the concept of pancreatic intraepithelial neoplasias (PanINs) and pancreatic intraductal papillary mucinous neoplasms (IMPNs), which were acknowledged as the precancerous lesions. Mount of studies on PanINs and IPMNs in respect to molecular biology, histopathology and clinicopathology showed that they were important phrases during the carcinogenesis of PDAC. Therefore, it may reveal the molecular mechanism of pancreatic cancer to explore the molecular aberrations harbored in the progression of PanINs or IPMNs toward PDAC.It is now well established that Wnt/beta-catenin signaling pathway has been a research hotspot in cancer development, for its pivotal role not only in normal life courses, such as biological development, cell-to-cell transport, and cell apoptosis, but also in tumorigenesis of several human organs when aberrantly activated. More recently, its role has been established in pancreatic development as well, but the specific mechanism is still not unclear, which is due to be lack of a comprehensive analysis of its components in such tumors. In this study, we carried out an immunohistochemical analysis of six key molecules of the Wnt/beta-catenin signaling pathway, including Wnt5a, APC,β-Catenin and the Wnt antagonist molecules secreted frizzled-related proteins-1 (sFRP-1), Dickkopf-1 (DKK-1) and Wnt inhibitory factor-1 (WIF-1), in a large series of PanINs, IPMNs and PDAC lesions, and furtherly, the correlation between protein expressions and clinicopathologic features was analyzed as well in order to evaluate their role in multistage pancreatic carcinogenesis and provide new clues for the diagnosis and treatment of PDAC.1. Difference analysis of Wnt5a expression in PanINs, IPMNs and PDAC.Objective: To detect the expression of Wnt5a protein in different pancreatic tissues (NP, PanINs, IPMNs and PDAC) and evaluate its significance during the carcinogenesis of PDAC, in order to provide new clues for the diagnosis and treatment of pancreatic cancer.Materials and Methods: Immunohistochemical detection of Wnt5a protein in 21 cases of normal pancreatic ducts, 73 cases of PanIN-1, 29 cases of PanIN-2, 16 cases of PanIN-3, 20 cases of IPMA, 13 cases of IPMB and 19 cases of IPMC and 50 cases of PDAC was proceeded with SP method; correlation between Wnt5a expression and clinicopathologic characteristics of PDAC was analyzed with Statistic Package for Social Science (SPSS).Results: IHCS of Wnt5a expression escalated with the severe tissue atypia along the progressive multistage: NP→PanIN-1→PanIN-2→PanIN-3 or NP→IPMA, IPMB→IPMC, PDAC. Wnt5a expression was significantly associated with tumor proliferation activity, distant metastasis, TNM staging and postoperative surial.Conclusion: Wnt5a expression enhancement is an early event in PDAC and its sustained expression or over-expression may affect proliferation, invasion and metastases of pancreatic cancer cell, and herald patient poor prognosis.2. Difference analysis ofβ-catenin expression in PanINs, IPMNs and PDAC.Objective: To detect the expression ofβ-catenin protein in different pancreatic tissues (NP, PanINs, IPMNs and PDAC) and evaluate its significance during the carcinogenesis of PDAC, in order to provide new clues for the diagnosis and treatment of pancreatic cancer.Materials and Methods: Immunohistochemical detection ofβ-catenin protein in 21 cases of normal pancreatic ducts, 73 cases of PanIN-1, 29 cases of PanIN-2, 16 cases of PanIN-3, 20 cases of IPMA, 13 cases of IPMB and 19 cases of IPMC and 50 cases of PDAC was proceeded with SP method; correlation betweenβ-catenin expression and clinicopathologic characteristics of PDAC was analyzed with SPSS. Results: IHCS ofβ-catenin membrane expression decreased with the severe tissue atypia along the progressive multistage: NP, PanIN-1→PanIN-2→PanIN-3, PDAC or NP→IPMA, IPMB→IPMC, PDAC, but the ectopic cytoplasm or nuclear expression ratio escalated.β-catenin membrane expression was significantly associated with tumor size, neural infiltration and lymphatic metastasis. Ectopic cytoplasm expression was significantly associated with tumor size. Ectopic nuclear expression was significantly associated with tumor differentiation. And the membrane or ectopic cytoplasm expression was significantly associated with postoperative surial.Conclusion: Reduced membranous and ectopic cytoplasm or nuclear expression ofβ-catenin play an important role during the development of PDAC and has an important value in the prognosis.3. Difference analysis of APC expression in PanINs, IPMNs and PDAC.Objective: To detect the expression of APC protein in different pancreatic tissues (NP, PanINs, IPMNs and PDAC) and evaluate its significance during the carcinogenesis of PDAC, in order to provide new clues for the diagnosis and treatment of pancreatic cancer.Materials and Methods: Immunohistochemical detection of APC protein in 21 cases of normal pancreatic ducts, 73 cases of PanIN-1, 29 cases of PanIN-2, 16 cases of PanIN-3, 20 cases of IPMA, 13 cases of IPMB and 19 cases of IPMC and 50 cases of PDAC was proceeded with SP method; correlation between APC expression and clinicopathologic characteristics of PDAC was analyzed with SPSS.Results: IHCS of APC expression escalated with the severe tissue atypia along the progressive multistage: NP→PanIN-1→PanIN-2→PanIN-3, but has no significant difference among IPMA, IPMB and IPMC. APC expression was significantly correlated with postoperative surial.Conclusion: Aberrant expression of Wnt5a is an early event in PDAC and its positive-expression indicates poor prognosis. However, the mechanism of APC aberrant expression needs to be further study. 4. Difference analysis of sFRP-1 expression in PanINs, IPMNs and PDAC.Objective: To detect the expression of sFRP-1 protein in different pancreatic tissues (NP, PanINs, IPMNs and PDAC) and evaluate its significance during the carcinogenesis of PDAC, in order to provide new clues for the diagnosis and treatment of pancreatic cancer.Materials and Methods: Immunohistochemical detection of sFRP-1 protein in 21 cases of normal pancreatic ducts, 73 cases of PanIN-1, 29 cases of PanIN-2, 16 cases of PanIN-3, 20 cases of IPMA, 13 cases of IPMB and 19 cases of IPMC and 50 cases of PDAC was proceeded with SP method; correlation between sFRP-1 expression and clinicopathologic characteristics of PDAC was analyzed with SPSS.Results: IHCS of sFRP-1 expression escalated with the severe tissue atypia along the progressive multistage: NP→PanIN-1→PanIN-2, PanIN-3, PDAC or NP→IPMA, IPMB→IPMC, PDAC. WIF expression was significantly associated with tumor differentiation, neural infiltration.Conclusion: sFRP-1 expression enhancement is an early event in PDAC and its high-expression is the important molecular characteristic of neural infiltration. 5. Difference analysis of WIF expression in PanINs, IPMNs and PDAC.Objective: To detect the expression of WIF protein in different pancreatic tissues (NP, PanINs, IPMNs and PDAC) and evaluate its significance during the carcinogenesis of PDAC, in order to provide new clues for the diagnosis and treatment of pancreatic cancer.Materials and Methods: Immunohistochemical detection of WIF protein in 21 cases of normal pancreatic ducts, 73 cases of PanIN-1, 29 cases of PanIN-2, 16 cases of PanIN-3, 20 cases of IPMA, 13 cases of IPMB and 19 cases of IPMC and 50 cases of PDAC was proceeded with SP method; correlation between WIF expression and clinicopathologic characteristics of PDAC was analyzed with SPSS.Results: IHCS of WIF expression escalated with the severe tissue atypia along the progressive multistage: NP→PanIN-1→PanIN-2→PanIN-3, PDAC or NP→IPMA, IPMB→IPMC, PDAC. WIF expression was significantly associated with tumor differentiation, neural infiltration and postoperative surial.Conclusion: WIF expression enhancement is an early event in PDAC and its high-expression indicates malignant biological behavior of PDAC, also, heralds patient poor prognosis.6. Difference analysis of DKK-1 expression in PanINs, IPMNs and PDAC.Objective: To detect the expression of DKK-1 protein in different pancreatic tissues (NP, PanINs, IPMNs and PDAC) and evaluate its significance during the carcinogenesis of PDAC, in order to provide new clues for the diagnosis and treatment of pancreatic cancer.Materials and Methods: Immunohistochemical detection of DKK-1 protein in 21 cases of normal pancreatic ducts, 73 cases of PanIN-1, 29 cases of PanIN-2, 16 cases of PanIN-3, 20 cases of IPMA, 13 cases of IPMB and 19 cases of IPMC and 50 cases of PDAC was proceeded with SP method; correlation between DKK-1 expression and clinicopathologic characteristics of PDAC was analyzed with SPSS. Results: Expression of DKK-1 could be hardly detection in all pancreatic ducts of different grades, and the positive expression only show in interstitial or vascular endothelial cells.Conclusion: DKK-1 may not participate in the PDAC progression or play a role through affecting the microenvironment.7. Correlations among the six genes expression and their independent predictive role in PDAC progression.Objective: To analyze the correlations among the Wnt5a, APC,β-Catenin, sFRP-1, DKK-1 and WIF-1 expression and explore their independent predictive role in PDAC progression.Materials and Methods: To collect the overall clinicopathologic reference of the 50 cases of PDAC, including the patient's age, gender, tumor size, tumor location, perineural invasion, venous invasion, grade of differentiation, proliferation activity, TNM staging, and postoperative surialResults:β-Catenin membrane expression was negatively correlated with APC positive expression, whileβ-Catenin ectopic cytoplasm expression was positively correlated with nuclear expression. Nerve infiltration, TNM staging, Wnt5a expression, APC expression and WIF-1 expression are the independent risk factors of postoperative surial.Conclusion: Aberrant activation of Wnt/β-Catenin signaling pathway promotes the development of PDAC. Wnt5a, APC and WIF-1 are important independent predictors for PDAC.8. SummaryThis study preceded the immunohistochemical detection of Wnt5a,β-Catenin,APC,sFRP-1,WIF-1,DKK-1 in different pancreatic tissues (normal, PanINs, IPMNs and PDAC), and analyzed the correlations of their expression with clinicopathologic variables of PDAC patients. The results showed that aberrant activation of Wnt/β-Catenin signaling pathway is one of the most important mechanisms of PDAC; aberrant expressions of Wnt5a,β-catenin,APC,sFRP-1,WIF-1 are early event during tumorigenesis of PDAC and are associated with the tumor malignant behaviors; Wnt5a,APC,WIF-1 are important independent predictors for postoperative surial; however, the specific mechanisms of APC,sFRP-1,WIF-1,DKK-1 need further study.
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