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‐sup...

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Bibliographic Details
Published in:Genes chromosomes & cancer 2004-06, Vol.40 (2), p.85-96
Main Authors: Wang, Fang, Denison, Stacy, Lai, Jin-Ping, Philips, Leslie A., Montoya, Damien, Kock, Norman, Schüle, Birgitt, Klein, Christine, Shridhar, Viji, Roberts, Lewis R., Smith, David I.
Format: Article
Language:English
Subjects:
Apoptosis - genetics
Apoptosis - physiology
Blotting, Western - methods
Carcinoma, Hepatocellular - chemistry
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - pathology
Cell Division - genetics
Cell Division - physiology
Chromosome Deletion
DNA, Neoplasm - genetics
Exons - genetics
Gene Dosage
Genes, Tumor Suppressor - physiology
Homozygote
Humans
Immunohistochemistry - methods
In Situ Hybridization, Fluorescence - methods
Liver Neoplasms - chemistry
Liver Neoplasms - genetics
Liver Neoplasms - pathology
Polymerase Chain Reaction - methods
RNA, Neoplasm - genetics
Transfection
Tumor Cells, Cultured
Ubiquitin-Protein Ligases - biosynthesis
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - immunology
Ubiquitin-Protein Ligases - physiology
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Summary: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. © 2004 Wiley‐Liss, Inc.
ISSN:1045-2257
1098-2264
DOI:10.1002/gcc.20020