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Blood, 15 October 2002, Vol. 100, No. 8, pp. 2950-2956
NEOPLASIA
Expression of Skp2, a p27Kip1 ubiquitin ligase, in
malignant lymphoma: correlation with p27Kip1 and
proliferation index
Megan S. Lim,
Ann Adamson,
Zhaosheng Lin,
Bayardo Perez-Ordonez,
Richard
C. K. Jordan,
Sheryl Tripp,
Sherrie L. Perkins, and
Kojo S. J. Elenitoba-Johnson
From the Department of Pathology and ARUP Institute for
Clinical and Experimental Pathology, University of Utah, Salt Lake
City; the Department of Anatomic Pathology, Sunnybrook Women's College
Health Sciences Centre, University of Toronto, ON, Canada; and
the Department of Oral Pathology, University of California, San
Francisco.
Reduced levels of p27Kip1 are frequent in human cancers
and have been associated with poor prognosis. Skp2, a component of the Skp1-Cul1-F-box protein (SCF) ubiquitin ligase complex, has been implicated in p27Kip1 degradation. Increased Skp2 levels
are seen in some solid tumors and are associated with reduced
p27Kip1. We examined the expression of these proteins using
single and double immunolabeling in a large series of lymphomas to
determine if alterations in their relative levels are associated with
changes in cell proliferation and lymphoma subgroups. We studied the
expression of Skp2 in low-grade and aggressive B-cell lymphomas
(n = 86) and compared them with p27Kip1 and the
proliferation index (PI). Fifteen hematopoietic cell lines and
peripheral blood lymphocytes were studied by Western blot analysis. In
reactive tonsils, Skp2 expression was limited to proliferating germinal
center and interfollicular cells. Skp2 expression in small lymphocytic
lymphomas (SLLs) and follicular lymphomas (FCLs) was
low (mean percentage of positive tumor cells, less than 20%) and was
inversely correlated (r =  0.67;
P < .0001) with p27Kip1 and positively
correlated with the PI (r = 0.82;
P < .005). By contrast, whereas most mantle cell
lymphomas (MCLs) demonstrated low expression of
p27Kip1 and Skp2, a subset (n = 6) expressed high
Skp2 (exceeding 20%) with a high PI (exceeding 50%). Skp2 expression
was highest in diffuse large B-cell lymphomas (DLBCLs) (mean,
22%) and correlated with Ki-67 (r = 0.55;
P < .005) but not with p27Kip1. Cytoplasmic
Skp2 was seen in a subset of aggressive lymphomas. Our data provide
evidence for p27Kip1 degradative function of Skp2 in
low-grade lymphomas. The absence of this relationship in aggressive
lymphomas suggests that other factors contribute to deregulation of
p27Kip1 expression in these tumors.
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