Reduced expression of p27Kip1 protein in relation to salivary adenoid cystic carcinoma metastasis

Abstract

Adenoid cystic carcinoma (ACC) is a malignant tumor of salivary gland origin. It tends to grow slowly but shows frequent recurrence and metastasis, ultimately with a poor outcome. Reduced expression of a cyclin-dependent kinase inhibitor, p27(Kip1), has been reported to correlate with poor survival for patients with various types of carcinoma. However, there has been no previous study reported of p27(Kip1) expression in ACC, to the authors' knowledge. To evaluate p27(Kip1) as a prognostic marker, the authors examined the immunohistochemical expression of p27(Kip1) protein in 29 ACCs and correlated its expression with clinicopathologic findings. Eleven pleomorphic adenomas (PAs) were also examined to compare the p27(Kip1) expression in benign and malignant salivary gland tumors. All PAs expressed p27(Kip1) at high levels, whereas 83% of ACCs (24 of 29) showed reduced expression of this protein. Furthermore, the expression levels were significantly lower in ACCs with metastasis than in those without metastasis. The authors also examined the expression of p27(Kip1) in 2 ACC cell lines (ACCh and ACC3) by Northern and Western blot analysis to elucidate the possible mechanism of p27(Kip1) reduction in ACC. Both ACCh and ACC3 expressed p27(Kip1) mRNA, but ACCh did not produce p27(Kip1) protein. In ACCh, the expression of p27(Kip1) protein was induced by treatment with a proteasome inhibitor. Overall, these findings suggest that reduced expression of p27(Kip1) may correlate with the development and progression of salivary ACC and can be an indicator of its malignant behavior. They also suggest that increased proteasome-mediated degradation may play an important role in this reduction of p27(Kip1) expression.