Parkin gene alterations in hepatocellular carcinoma.
The Parkin gene is an extremely large gene (1.5 Mb) within the highly unstable FRA6E common fragile site (CFS) region, which is frequently altered in ovarian, breast, and hepatocellular carcinomas. Because Parkin/FRA6E has genomic similarities to FHIT/FRA3B and WWOX/FRA16D, two other large tumor-suppressor genes that are within CFS regions, we were interested in characterizing Parkin gene alterations and their possible association with cancer. After analyzing 50 cancer-derived cell lines including 11 hepatocellular carcinoma (HCC) cell lines, we found that one HCC cell line, PLC/PRF/5, had a detectable homozygous deletion encompassing exon 3. Using quantitative duplex PCR and fluorescence in situ hybridization analysis to characterize the copy number changes of Parkin exons in HCC cell lines, we found that 4 of 11 HCC cell lines had heterozygous deletions of Parkin exons and one, Hep3B, had an exon duplication. Parkin protein expression was significantly decreased or absent in all 11 HCC cell lines. Furthermore, more than 50% of HCC primary tumors had decreased Parkin expression compared to that in normal liver tissue. Parkin gene-transfected PLC5 and Hep3B cells grew more slowly than vector-only transfectants and also showed increased sensitivity to apoptosis induced by cell-cycle inhibitors. Therefore, we suggest that Parkin may be involved in tumor suppression and that the loss of Parkin contributes to the development of hepatocarcinoma.
Wang
Fang
F
Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Denison
Stacy
S
Lai
Jin-Ping
JP
Philips
Leslie A
LA
Montoya
Damien
D
Kock
Norman
N
Schüle
Birgitt
B
Klein
Christine
C
Shridhar
Viji
V
Roberts
Lewis R
LR
Smith
David I
DI
D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western / Q000379:methods; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D002872:Chromosome Deletion; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons / Q000235:genetics; D018628:Gene Dosage; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008113:Liver Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction / Q000379:methods; D012334:RNA, Neoplasm / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology / Q000502:physiology
D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein