Dataset Information

Upregulation of nucleoprotein AHNAK is associated with poor outcome of pancreatic ductal adenocarcinoma prognosis via mediating epithelial-mesenchymal transition.

ABSTRACT: The nucleoprotein AHNAK (AHNAK) is a large scaffold protein that is involved in several biological processes. Previous studies have suggested a possible relation between AHNAK and the epithelial-mesenchymal transition (EMT). However, the role of AHNAK in pancreatic ductal adenocarcinoma (PDAC) has not been unveiled. The present study focuses on identifying the potential value of the biological effects of AHNAK in PDAC, which is one of the most lethal malignancies. Bioinformatic analysis was carried for driver gene prediction, and we proved that AHNAK was a driver gene of pancreatic adenocarcinoma and a predictor of poor outcomes of PDAC by clinical characteristics analysis and in vitro experiments. High AHNAK expression was associated with short disease-free survival and poor overall survival. In vitro assays showed that AHNAK was associated with cell proliferation and migration, and a positive relation was observed between AHNAK and the EMT. In conclusion, AHNAK is a crucial biomarker that may promote cellular proliferation and migration and thus impact PDAC outcomes via the EMT, which suggests that AHANK might be a potential target for PDAC.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC6636292 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Upregulation of nucleoprotein AHNAK is associated with poor outcome of pancreatic ductal adenocarcinoma prognosis via mediating epithelial-mesenchymal transition.

Zhang Zhiwen Z Liu Xiaoding X Huang Rui R Liu Xuguang X Liang Zhiyong Z Liu Tonghua T

Journal of Cancer 20190610 16

The nucleoprotein AHNAK (AHNAK) is a large scaffold protein that is involved in several biological processes. Previous studies have suggested a possible relation between AHNAK and the epithelial-mesenchymal transition (EMT). However, the role of AHNAK in pancreatic ductal adenocarcinoma (PDAC) has not been unveiled. The present study focuses on identifying the potential value of the biological effects of AHNAK in PDAC, which is one of the most lethal malignancies. Bioinformatic analysis was carr ...[more]

PMID: 31333803

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Project description:BackgroundEpidermal growth factor receptor (EGFR) is highly expressed in pancreatic ductal adenocarcinoma (PDAC) and is involved in tumorigenesis and development. However, EGFR expression alone has limited clinical and prognostic significance. Recently, the cross-talk between EGFR and G-protein-coupled chemokine receptor CXCR4 has become increasingly recognized.MethodsIn the present study, immunohistochemical staining of EGFR and CXCR4 was performed on paraffin-embedded specimens from 131 patients with surgically resected PDAC. Subsequently, the associations between EGFR expression, CXCR4 expression, EGFR/CXCR4 coexpression and clinicopathologic factors were assessed, and survival analyses were performed.ResultsIn total, 64 (48.9%) patients expressed EGFR, 68 (51.9%) expressed CXCR4, and 33 (25.2%) coexpressed EGFR and CXCR4. No significant association between EGFR and CXCR4 expression was observed (P = 0.938). EGFR expression significantly correlated with tumor differentiation (P = 0.031), whereas CXCR4 expression significantly correlated with lymph node metastasis (P = 0.001). EGFR/CXCR4 coexpression was significantly associated with lymph node metastasis (P = 0.026), TNM stage (P = 0.048), and poor tumor differentiation (P = 0.004). By univariate survival analysis, both CXCR4 expression and EGFR/CXCR4 coexpression were significant prognostic factors for poor disease-free survival (DFS) and overall survival (OS). Moreover, EGFR/CXCR4 coexpression significantly increased the hazard ratio for both recurrence and death compared with EGFR or CXCR4 protein expression alone. Multivariate survival analysis demonstrated that EGFR/CXCR4 coexpression was an independent prognostic factor for DFS (HR = 2.33, P<0.001) and OS (HR = 2.48, P = 0.001).ConclusionsIn conclusion, our data indicate that although EGFR expression alone has limited clinical and prognostic significance, EGFR/CXCR4 coexpression identified a subset of PDAC patients with more aggressive tumor characteristics and a significantly worse prognosis. Our results suggest a potentially important "cross-talk" between CXCR4 and EGFR intracellular pathways and indicate that the simultaneous inhibition of these pathways might be an attractive therapeutic strategy for PDAC.

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is characterized by an important heterogeneity, reflected by different clinical outcomes and chemoresistance. During carcinogenesis, tumor cells display aberrant glycosylated structures, synthetized by deregulated glycosyltransferases, supporting the tumor progression. In this study, we aimed to determine whether PDAC could be stratified through their glycosyltransferase expression profiles better than the current binary classification (basal-like and classical) in order to improve detection of patients with poor prognosis.MethodsBioinformatic analysis of 169 glycosyltransferase RNA sequencing data were performed for 74 patient-derived xenografts (PDX) of resected and unresectable tumors. The Australian cohort of International Cancer Genome Consortium and the microarray dataset from Puleo patient's cohort were used as independent validation datasets.FindingsNew PDAC stratification based on glycosyltransferase expression profile allowed to distinguish different groups of patients with distinct clinical outcome (p-value = 0.007). A combination of 19 glycosyltransferases differentially expressed in PDX defined a glyco-signature, whose prognostic value was validated on datasets including resected whole tumor tissues. The glyco-signature was able to discriminate three clusters of PDAC patients on the validation cohorts, two clusters displaying a short overall survival compared to one cluster having a better prognosis. Both poor prognostic clusters having different glyco-profiles in Puleo patient's cohort were correlated with stroma activated or desmoplastic subtypes corresponding to distinct microenvironment features (p-value < 0.0001). Besides, differential expression and enrichment analyses revealed deregulated functional pathways specific to different clusters.InterpretationThis study identifies a glyco-signature relevant for a prognostic use, potentially applicable to resected and unresectable PDAC. Furthermore, it provides new potential therapeutic targets.FundingThis work was supported by INCa (Grants number 2018-078 and 2018-079), Fondation ARC (Grant number ARCPJA32020070002326), Cancéropôle PACA, DGOS (labelization SIRIC, Grant number 6038), Amidex Foundation and Ligue Nationale Contre le Cancer and by institutional fundings from INSERM and the Aix-Marseille Université.

Dataset Information

Upregulation of nucleoprotein AHNAK is associated with poor outcome of pancreatic ductal adenocarcinoma prognosis via mediating epithelial-mesenchymal transition.

Publications

Upregulation of nucleoprotein AHNAK is associated with poor outcome of pancreatic ductal adenocarcinoma prognosis via mediating epithelial-mesenchymal transition.

Similar Datasets

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