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-ln is a protein scaffo ld which spans the whole cell, and several lines of evidence suggest that t his structural frame represents also a functional unit, which could be invo lved in the epigenetic control of cancer development. Here we report the ch aracterization by high resolution two-dimensional gel electrophoresis and W estern blot analysis of the NM-IF complex isolated from prostate cancer (PC a); tumor-associated proteins were identified by comparing the electrophore tic patterns with those of normal human prostate (NHP). Extensive changes i n the expression of both the NM and IF proteins occur; they are, however, r elated in a different way to tumor progression. Poorly differentiated PCa ( Gleason score 8-9) shows a strong down regulation of several constitutive c ytokeratins (CKs 8, 18, and 19); their expression significantly (P < 0.05) decreases with respect to both NHP and benign prostatic hyperplasia (BPH) a nd, more interestingly, also with respect to moderately (Gleason score 6-7) and well (Gleason score 4-5) differentiated tumors. Moreover, we have iden tified a tumor-associated species which is present in all of the tumors exa mined, 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 fragm ent of CK8. At variance with these continuing alterations in the Expression , the NM proteins undergo stepwise changes correlating with the level of di fferentiation. The development of less differentiated tumors is characteriz ed by the appearance of several new proteins and by the decrease in the exp ression 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 freq uency is less than one, acid decreases With increasing the level of differe ntiation. When tumors of increasing Gleason score are compared with NHP a d ramatic increase in the complexity of the protein patterns is observed, ind icating 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 protein s. (C) 2000 Wiley-Liss, Inc.