RESUMEN
The c-Jun amino-terminal kinase (JNK) pathway seems to play important roles in the pathogenesis of several tumors, but its significance in extramammary Paget disease (EMPD) has not been investigated yet. The purpose of the study was to investigate the potential contribution of the JNK-associated molecules, such as hematopoietic progenitor kinase 1 (HPK1), mitogen-activated protein/extracellular signal-related protein kinase kinase kinase1 (MEKK1), transforming growth factor-ß activated kinase 1 (TAK1), and phosphomitogen-activated protein kinase kinase 4 (p-MKK4) to the development of EMPD. Thirty-five paraffin-embedded EMPD specimens were subjected to immunohistochemical staining for HPK1, MEKK1, TAK1, and p-MKK4. All the 35 EMPD, including 13 dermal invasive EMPD and 2 lymph node metastasis, showed cytoplasmic overexpression of HPK1, MEKK1, and p-MKK4. The expression (%positive cells) of HPK1, MEKK1, and p-MKK4 in EMPD (92.3% ± 8.6%, 92.9% ± 8.6%, and 92.7% ± 7.4%, respectively) were significantly higher than in normal eccrine sweat gland cells (51.6% ± 10.4%, 44.7% ± 11.7%, 0% ± 0%). In addition, the expression of HPK1-, MEKK1-, and p-MKK4 in invasive EMPD was significantly higher than in noninvasive EMPD. Meanwhile, the expression of TAK1 was basically low and no significantly different between EMPD and normal controls. In conclusion, these results indicate that JNK pathway may play a role in the pathogenesis of EMPD.
Asunto(s)
MAP Quinasa Quinasa 4/biosíntesis , Quinasa 1 de Quinasa de Quinasa MAP/biosíntesis , Enfermedad de Paget Extramamaria/enzimología , Enfermedad de Paget Extramamaria/patología , Proteínas Serina-Treonina Quinasas/biosíntesis , Adulto , Anciano , Biomarcadores de Tumor/análisis , Femenino , Humanos , Inmunohistoquímica , Quinasas Quinasa Quinasa PAM/biosíntesis , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , PronósticoAsunto(s)
Adenocarcinoma Sebáceo/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Enfermedad de Paget Extramamaria/metabolismo , Poroma/metabolismo , Neoplasias de las Glándulas Sebáceas/metabolismo , Glándulas Sebáceas/metabolismo , Neoplasias de las Glándulas Sudoríparas/metabolismo , Glándulas Sudoríparas/metabolismo , Siringoma/metabolismo , Adenocarcinoma Sebáceo/química , Adenocarcinoma Sebáceo/patología , Dermatosis Facial/metabolismo , Dermatosis Facial/patología , Humanos , Hiperplasia/metabolismo , Hiperplasia/patología , Inmunohistoquímica , Proteínas de la Membrana/análisis , Proteínas del Tejido Nervioso/análisis , Enfermedad de Paget Extramamaria/química , Enfermedad de Paget Extramamaria/patología , Poroma/química , Poroma/patología , Neoplasias de las Glándulas Sebáceas/química , Neoplasias de las Glándulas Sebáceas/patología , Glándulas Sebáceas/química , Glándulas Sebáceas/patología , Neoplasias de las Glándulas Sudoríparas/química , Neoplasias de las Glándulas Sudoríparas/patología , Glándulas Sudoríparas/química , Glándulas Sudoríparas/patología , Siringoma/química , Siringoma/patologíaRESUMEN
BACKGROUND: Neurotrophin (NT) systems appear to play important roles in the pathogenesis of several tumors, but their expression in extramammary Paget's disease (EPD) has not been investigated. METHODS: Thirty-four paraffin-embedded EPD specimens (32 primary EPD and 2 metastatic to lymph nodes) were subject to immunohistochemical staining for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT3, NT4, their high-affinity receptors (TrkA, TrkB and TrkC) and the common low-affinity receptor, p75 NT receptor (p75). RESULTS: All 34 EPD specimens, including 2 metastatic to lymph nodes, showed cytoplasmic overexpression of NGF, BDNF, TrkA and TrkB. The expression (% positive cells) of NGF, BDNF, NT3, NT4, TrkA and TrkB (81.6 ± 14.9, 86.0 ± 10.4, 89.6 ± 14.9, 87.8 ± 17.9, 83 ± 14.4 and 86.2 ± 11.7%) in EPD was significantly higher than in normal skin (21.6 ± 6.5, 27.6 ± 4.5, 19.7 ± 10.1, 8.2 ± 10.0, 25.0 ± 5.3 and 25.4 ± 6.4%), and the expression of these factors in invasive EPD was significantly higher than in noninvasive EPD. Interestingly, Paget cells were negative for p75 and TrkC in all the 34 EPD specimens. CONCLUSIONS: These results suggest that overexpression of NGF, BDNF and their high-affinity receptors (TrkA and TrkB) might play a role in the pathogenesis of EPD.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor de Crecimiento Nervioso/metabolismo , Enfermedad de Paget Extramamaria/metabolismo , Receptores de Factor de Crecimiento Nervioso/metabolismo , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunohistoquímica , Metástasis Linfática , Masculino , Persona de Mediana EdadRESUMEN
Development of neurofibroma (NF) and its malignant counterpart, malignant peripheral nerve sheath tumor (MPNST), is a hallmark of type I neurofibromatosis (NF1). Newly identified glycoprotein neuronatin (Nnat) is predominantly expressed in the fetal central and peripheral nervous systems and is gradually diminished according to the neural maturation. However, its expression in NFs and MPNSTs is unknown. Since an overexpression of tenascin-C (Tn-C), an extracellular matrix component, has been observed in neural malignancies, we investigated the immunohistological expressions of Nnat and Tn-C in NFs and MPNSTs, and compared their expression with that of the proliferation marker Ki-67 to possibly distinguish MPNSTs from ordinal NFs. Standard immunohistological procedure was performed for Nnat, Tn-C and Ki-67 in 9 sporadic NFs, 15 diffuse NFs (NF1), 15 plexiform NFs (NF1) and 6 MPNSTs (NF1), as well as 5 normal skins. All of the MPNSTs showed positive staining for Nnat, Tn-C and Ki-67, in sharp contrast to completely negative staining in all sporadic or NF-1-derived NFs. The aberrant expression of Nnat and Tn-C was a useful marker for distinguishing MPNSTs from benign NFs.