Expression of cyclin-dependent kinase inhibitor p27/Kip1 and AP-1 coactivator p38/Jab1 correlates with differentiation of embryonal rhabdomyosarcoma

Abstract

Cyclin-dependent kinase (CDK) inhibitor p27/Kip1 (p27) is a diagnostic and prognostic marker of various malignancies. Low expression of p27 reflects poor differentiation and poor prognosis, and an inverse correlation between the expression of p27 and degree of tumor malignancy has been reported. Because p27 mutation is extremely rare in human tumors, it is important to study the expression of p27 and its inactivator, p38/Jab1 (JAB1). Here we analyzed the expression of p27 and JAB1 by immunohistochemistry in embryonal rhabdomyosarcoma (E-RMS). We first confirmed the expression of p27 and JAB1 in normal human tonsillar epithelium, and observed a coordinated expression pattern depending on cell differentiation. Subsequently, specimens of eight poorly- and three well-differentiated E-RMS were examined for the expression of p27 and JAB1. The analyses revealed that four out of eight poorly-differentiated E-RMS were negative for p27, with positivity for nuclear JAB (NJAB) (-/+ for p27/NJAB) in three and negativity for any JAB-1 expression (-/-) in one. The remaining four poorly-differentiated E-RMS expressed p27 in the nuclei, together with predominant NJAB (+/+). In three well-differentiated E-RMS, only one expressed nuclear p27 and all of these three expressed no NJAB (+/- for p27/NJAB), but expressed predominant cytoplasmic JAB1 (CJAB). These findings suggest that JAB1 may play an important role in determining the differentiation stage of rhabdomyosarcoma cells by modulating the activity of CDK inhibitor p27.