Changes in the expression of cytokeratins and nuclear matrix proteins are correlated with the level of differentiation in human prostate cancer.

The nuclear matrix-intermediate filament complex (NM-IF) is a protein scaffold which spans the whole cell, and several lines of evidence suggest that this structural frame represents also a functional unit, which could be involved in the epigenetic control of cancer development. Here we report the characterization by high resolution two-dimensional gel electrophoresis and Western blot analysis of the NM-IF complex isolated from prostate cancer (PCa); tumor-associated proteins were identified by comparing the electrophoretic patterns with those of normal human prostate (NHP). Extensive changes in the expression of both the NM and IF proteins occur; they are, however, related in a different way to tumor progression. Poorly differentiated PCa (Gleason score 8-9) shows a strong down regulation of several constitutive cytokeratins (CKs 8, 18, and 19); their expression significantly (P < 0.05) decreases with respect to both NHP and benign prostatic hyperplasia (BPH) and, more interestingly, also with respect to moderately (Gleason score 6-7) and well (Gleason score 4-5) differentiated tumors. Moreover, we have identified a tumor-associated species which is present in all of the tumors examined, systematically absent in NHP and occurs only in a few samples of BPH; this polypeptide, of M(r) 48,000 and pI 6.0, represent a proteolytic fragment of CK8. At variance with these continuing alterations in the expression, the NM proteins undergo stepwise changes correlating with the level of differentiation. The development of less differentiated tumors is characterized by the appearance of several new proteins and by the decrease in the expression of others. Six proteins were found to be expressed with a frequency equal to one in poorly differentiated tumor, namely in all the samples of tumor examined, while in moderately and well differentiated tumors the frequency is less than one, and decreases with increasing the level of differentiation. When tumors of increasing Gleason score are compared with NHP a dramatic increase in the complexity of the protein patterns is observed, indicating that tumor dedifferentiation results in a considerable increase in the phenotypic diversity. These results suggest that tumor progression can be characterized using an appropriate subset of tumor-associated NM proteins. Copyright 2000 Wiley-Liss, Inc.