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1.
Virchows Arch ; 475(1): 95-104, 2019 Jul.
Article in English | MEDLINE | ID: mdl-30903272

ABSTRACT

The aim of this study was to evaluate the nuclear expression of histone methyltransferase enhancer of zeste homolog 2 (EZH2) in endocervical neoplastic lesions such as invasive endocervical adenocarcinoma (ECA) and cervical in situ adenocarcinoma (AIS) in comparison with normal endocervix and non-neoplastic counterparts. A total of 54 consecutive neoplastic cases (37 ECA, 17 AIS) and 32 non-neoplastic endocervical lesions (15 reactive atypia, 9 microglandular hyperplasia, 3 tuboendometrioid metaplasia, 3 tunnel cluster, 2 endometriosis) were included in the study with adjacent normal endocervix if present. EZH2 immunoreactivity was evaluated semiquantitatively by three independent experts in lesions and adjacent normal glandular epithelium as well. EZH2 expression was defined robust if at least two of the three experts rated partial or diffuse positivity. Robust EZH2 expression was statistically compared among the neoplastic, non-neoplastic, and normal glandular epithelium samples. Diagnostic test capability of robust EZH2 expression was calculated. Fifty-three out of the 54 neoplastic cases (98%) showed robust EZH2 expression. Robust EZH2 expression was significantly less often (4 out of 32 cases, 12.5%) found in the non-neoplastic endocervical lesions (p < 0.0001) and never (0 out of 66 samples) in the adjacent normal glandular epithelium. Robust EZH2 overexpression had a sensitivity and specificity of over 95% in detecting neoplastic lesions versus non-neoplastic lesions or normal glandular epithelium. EZH2 may play a role in the pathogenesis of endocervical neoplasia, and the detection of robust expression of EZH2 might be a useful differential diagnostic tool in problematic endocervical lesions in histology and cytology as well.


Subject(s)
Adenocarcinoma in Situ/enzymology , Adenocarcinoma/enzymology , Biomarkers, Tumor/analysis , Enhancer of Zeste Homolog 2 Protein/analysis , Uterine Cervical Dysplasia/enzymology , Uterine Cervical Neoplasms/enzymology , Adenocarcinoma/pathology , Adenocarcinoma in Situ/pathology , Adult , Aged , Aged, 80 and over , Cell Nucleus/enzymology , Cell Nucleus/pathology , Female , Humans , Immunohistochemistry , Middle Aged , Predictive Value of Tests , Uterine Cervical Neoplasms/pathology , Uterine Cervical Dysplasia/pathology
2.
Pancreas ; 43(8): 1256-63, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25072283

ABSTRACT

OBJECTIVES: A functional vacuolar adenosine triphosphatase (v-ATPase) complex regulates canonical Wnt/ß-catenin signaling. The goal of this study was to identify the distribution of the v-ATPase in human and murine models of pancreatic intraepithelial neoplasms (PanINs) and assess its role in Wnt/ß-catenin signaling. METHODS: We evaluated the immunolabeling pattern of the v-ATPase in human PanIN specimens and murine PanIN-1 and PanIN-2 lesions obtained from Ptf1a(Cre/+); LSL-Kras(G12D) mice. Wnt/ß-catenin signaling was interrogated in primary PanIN cells by examining the phosphorylated levels of its surface coreceptor, low-density lipoprotein receptor-related protein-6 (LRP6), and its intracellular effector, nonphosphorylated ß-catenin. The response of primary PanIN cells to epidermal growth factor (EGF) was assessed in the absence and presence of the v-ATPase inhibitor, concanamycin. RESULTS: In advanced (PanIN-2), but not early (PanIN-1), lesions, the v-ATPase assumed a polarized phenotype. Blocking the v-ATPase disrupted Wnt/ß-catenin signaling in primary PanIN cells despite significantly higher levels of the total and activated Wnt cell surface coreceptor, LRP6. Vacuolar adenosine triphosphatase blockade significantly decreased the total and activated levels of EGF receptor, a determinant of PanIN progression. The activation of EGF receptor and its intracellular mediator, p44/42 mitogen-activated protein kinase, was also reduced by v-ATPase blockade. This led to diminished proliferation in response to EGF ligand. CONCLUSIONS: The v-ATPase regulates Wnt/ß-catenin and EGF receptor signaling in PanINs.


Subject(s)
Carcinoma, Pancreatic Ductal/enzymology , Membrane Proteins/analysis , Neoplasm Proteins/analysis , Pancreatic Neoplasms/enzymology , Vacuolar Proton-Translocating ATPases/analysis , Wnt Signaling Pathway/physiology , Adenocarcinoma in Situ/enzymology , Adenocarcinoma in Situ/ultrastructure , Alcian Blue , Animals , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/ultrastructure , Cell Line, Tumor , Cell Polarity , Disease Progression , Epidermal Growth Factor/pharmacology , ErbB Receptors/analysis , ErbB Receptors/drug effects , Humans , Islets of Langerhans/enzymology , Islets of Langerhans/ultrastructure , Low Density Lipoprotein Receptor-Related Protein-6/analysis , Mice , Mice, Mutant Strains , Mitogen-Activated Protein Kinase 3/analysis , Mitogen-Activated Protein Kinase 3/physiology , Neoplasm Grading , Neoplasm Proteins/physiology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/ultrastructure , Protein Transport , Staining and Labeling , Vacuolar Proton-Translocating ATPases/physiology
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