title: Parkin gene alterations in hepatocellular carcinoma.
abstract: 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.
authors.affiliation: Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Stacy
authors.initials: S
authors.lastname: Denison
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Lai
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Philips
authors.forename: Damien
authors.initials: D
authors.lastname: Montoya
authors.forename: Norman
authors.initials: N
authors.lastname: Kock
authors.forename: Birgitt
authors.initials: B
authors.lastname: Schüle
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.forename: Viji
authors.initials: V
authors.lastname: Shridhar
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
authors.forename: David I
authors.initials: DI
authors.lastname: Smith
mesh_terms: 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
chemical_list: D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein