Alterations in PMS2, MSH2 and MLH1 expression in human prostate cancer.
DNA mismatch repair (MMR) is involved in the post-replication correction of errors due to misincorporated nucleotides or DNA slippage during DNA synthesis. We previously reported the reduction or loss of MMR protein expression in human prostate cancer cell lines and some primary tumors. In the present report, we further demonstrate the involvement of defects of MMR in the pathogenesis of prostate cancer. Immunohistochemical analysis of 39 formalin-fixed, paraffin-embedded human prostate tumors, showed reduction or absence of MMR protein expression (MLH1, MSH2, PMS2) in the epithelium of prostate tumor foci compared to normal adjacent prostate tissue. The reduction or absence of the PMS2 and MSH2 (but not MLH1) protein was correlated to the differentiation of the tumor. Poorly differentiated tumors showed greater loss of these two proteins than the well differentiated tumors (P<0.05). We previously reported that microsatellite instability was detectable by a beta-galactosidase restoration mutation assay in the prostate cancer cell lines DU145, PC3, LNCaP, p67SV40T, M2182, and M12. In this study, we detected the insertion or deletion of one nucleotide in the mononucleotide repeats located within the coding regions of BAX gene in DU145, and TGFbetaRII in M12 cells. In addition, we used an in vitro model of defective MMR to demonstrate that microsatellite instability can be induced in an otherwise stable cancer cell line by transfection with a dominant negative fragment of PMS2. These results suggest that defects in MMR may result in MSI in the secondary genes in prostate cancer. From these results, we conclude that loss of MMR function can produce MSI and target some secondary genes containing microsatellites in their coding regions. These series of events may play important roles in the development of human prostate cancer.
Chen
Yian
Y
Laboratory of Cancer Genomics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
Wang
Jiansong
J
Fraig
Mostafa M
MM
Henderson
Kelly
K
Bissada
Nabil K
NK
Watson
Dennis K
DK
Schweinfest
Clifford W
CW
D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D020137:Base Pair Mismatch / Q000235:genetics*; D001483:Base Sequence; D002352:Carrier Proteins; D017931:DNA Primers; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes