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OBJECTIVE: To investigate the immunohistochemical (IHC) expression of the ErbB/HER family in primary vulvar squamous cell carcinoma (VSCC). METHODS: We analyzed a series of 125 patients who were surgically treated for VSCC from January 1980 to June 2016. All cases had lymph node (LN) staging and 80 had LN metastasis. A tissue microarray was built for epidermal growth factor receptor (EGFR), HER2, HER3, and HER4 IHC staining. RESULTS: In the primary tumor we found positive expressions for EGFR, HER2, HER3, and HER4 in 5%, 0.9%, 0.9%, and 22.8%, respectively. For the LN metastasis, expressions of EGFR and HER4 were positive in 22.2% and 39.1%, respectively. No cases had positive staining for HER2 and HER3 in the LN metastasis. For HER4, positive expression correlated with smaller tumor sizes (P = 0.02). However, positive HER4 was related to adverse prognostic factors such as: histological grade (P = 0.012), presence of lymphovascular space invasion (40.9% vs 16.2%; P = 0.035), and perineural invasion (57.1% vs 16.7%; P = 0.006). Notably, all cases with LN metastasis had positive HER4 in the primary tumor (P < 0.001). ErbB/HER family expression was not related to worse survival. CONCLUSION: EGFR, HER2, and HER3 were infrequently expressed in VSCC by IHC. HER4 IHC expression was found in 22.8% of cases and was related to adverse prognostic factors.
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Neoplasias de la Vulva , Femenino , Humanos , Inmunohistoquímica , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Receptor ErbB-4/metabolismoRESUMEN
BACKGROUND: The epidermal growth factor receptors participate in the physiological processes such as regulation of morphogenesis, proliferation and cell migration, but when overexpressed or overactivated they may play an important role in neoplastic progression. Melanoma is the most aggressive skin neoplasm and is characterized by elevated invasion and low survival rates in both humans and dogs. In human melanomas the overexpression of EGFR, HER3 or HER4 is associated with poor prognosis. In canine melanomas the epidermal growth factor receptors expression has not been evaluated. Therefore, this study evaluated the expression of epidermal growth factor receptors by immunohistochemistry and investigated their relationship with morphological characteristics and proliferative indices in cutaneous and oral canine melanoma. RESULTS: In cutaneous melanoma an increased proliferative index was associated with increased cytoplasmic HER4 and reduced EGFR and HER3 protein expression. In oral melanomas, membranous HER2 protein expression correlated with occurrence of emboli, but ERBB2 gene amplification wasn't observed. CONCLUSION: Thus, our work evidenced the relationship between HER4 and the stimulus to cell proliferation in cutaneous melanomas, in addition to the relationship between HER2 and the occurrence of emboli in oral melanomas.
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Receptores ErbB/metabolismo , Melanoma/veterinaria , Neoplasias de la Boca/veterinaria , Animales , Proliferación Celular , Perros , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica , Inmunohistoquímica/veterinaria , Melanoma/metabolismo , Neoplasias de la Boca/metabolismo , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo , Receptor ErbB-4/genética , Receptor ErbB-4/metabolismo , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/veterinaria , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: Myocardial stretch increases force biphasically: the Frank-Starling mechanism followed by the slow force response (SFR). Based on pharmacological strategies, we proposed that epidermal growth factor (EGF) receptor (EGFR or ErbB1) activation is crucial for SFR development. Pharmacological inhibitors could block ErbB4, a member of the ErbB family present in the adult heart. We aimed to specifically test the role of EGFR activation after stretch, with an interference RNA incorporated into a lentiviral vector (small hairpin RNA [shRNA]-EGFR). METHODS AND RESULTS: Silencing capability of p-shEGFR was assessed in EGFR-GFP transiently transfected HEK293T cells. Four weeks after lentivirus injection into the left ventricular wall of Wistar rats, shRNA-EGFR-injected hearts showed ≈60% reduction of EGFR protein expression compared with shRNA-SCR-injected hearts. ErbB2 and ErbB4 expression did not change. The SFR to stretch evaluated in isolated papillary muscles was ≈130% of initial rapid phase in the shRNA-SCR group, while it was blunted in shRNA-EGFR-expressing muscles. Angiotensin II (Ang II)-dependent Na+/H+ exchanger 1 activation was indirectly evaluated by intracellular pH measurements in bicarbonate-free medium, demonstrating an increase in shRNA-SCR-injected myocardium, an effect not observed in the silenced group. Ang II- or EGF-triggered reactive oxygen species production was significantly reduced in shRNA-EGFR-injected hearts compared with that in the shRNA-SCR group. Chronic lentivirus treatment affected neither the myocardial basal redox state (thiobarbituric acid reactive substances) nor NADPH oxidase activity or expression. Finally, Ang II or EGF triggered a redox-sensitive pathway, leading to p90RSK activation in shRNA-SCR-injected myocardium, an effect that was absent in the shRNA-EGFR group. CONCLUSIONS: Our results provide evidence that specific EGFR activation after myocardial stretch is a key factor in promoting the redox-sensitive kinase activation pathway, leading to SFR development.
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Receptores ErbB/genética , Corazón/fisiopatología , Miocardio/metabolismo , Angiotensina II/farmacología , Animales , Receptores ErbB/metabolismo , Silenciador del Gen , Proteínas Fluorescentes Verdes , Células HEK293 , Corazón/efectos de los fármacos , Humanos , Concentración de Iones de Hidrógeno , Masculino , ARN Interferente Pequeño , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-4/metabolismo , Intercambiador 1 de Sodio-Hidrógeno/metabolismo , Vasoconstrictores/farmacologíaRESUMEN
ErbB4 is an oncogene belonging to the epidermal growth factor receptor family and contributes to the occurrence and development of multiple cancers, such as gastric, breast, and colorectal cancers. Therefore, studies of the regulation of ErbB4 in cancerigenic pathway will advance molecular targeted therapy. Advanced bioinformatic analysis softwares, such as ExPASy, Predictprotei, QUARK, and I-TASSER, were used to analyze the regulatory mechanism after ErbB4 gene mutation in terms of amino acid sequence, primary, secondary, and tertiary structure of the protein and upstream-downstream receptor/ligands. Mutation of the 19th and 113th amino acids at the carboxyl terminus of ErbB4 protein did not affect its biological nature, but its secondary structure changed and protein binding sites were near 2 mutational sites; moreover, after mutation introduction, additional binding sites were observed. Tertiary structure modeling indicated that local structure of ErbB4 was changed from an α helical conformation into a ß chain folding structure; the α helical conformation is the functional site of protein, while active sites are typically near junctions between helical regions, thus the helical structures are easily destroyed and change into folding structures or other structures after stretching. Mutable sites of ErbB4 is exact binding sites where dimer formed with other epidermal growth factor family proteins; mutation enabled the ErbB4 receptor to bind to neuregulin 1 ligand without dimer formation, disrupting the signal transduction pathway and affecting ErbB4 function.