title: Hematopoietic progenitor kinase 1, mitogen-activated protein/extracellular signal-related protein kinase kinase kinase 1, and phosphomitogen-activated protein kinase kinase 4 are overexpressed in extramammary Paget disease.
abstract: 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-β 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.
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yue
authors.initials: Y
authors.lastname: Qian
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takeuchi
authors.forename: Long
authors.initials: L
authors.lastname: Dugu
authors.forename: Gaku
authors.initials: G
authors.lastname: Tsuji
authors.forename: Lining
authors.initials: L
authors.lastname: Xie
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakahara
authors.forename: Masakazu
authors.initials: M
authors.lastname: Takahara
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Moroi
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Tu
authors.forename: Masutaka
authors.initials: M
authors.lastname: Furue
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D048670:MAP Kinase Kinase 4 / Q000096:biosynthesis*; D048728:MAP Kinase Kinase Kinase 1 / Q000096:biosynthesis*; D020930:MAP Kinase Kinase Kinases / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010145:Paget Disease, Extramammary / Q000201:enzymology* / Q000473:pathology*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D014408:Biomarkers, Tumor; D048670:MAP Kinase Kinase 4; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; D017346:Protein Serine-Threonine Kinases; D000099151:MAP Kinase Kinase Kinase 7; C102102:hematopoietic progenitor kinase 1; C482576:MAP3K1 protein, human; C482559:MAP2K4 protein, human