Alterations of the tumor suppressor gene Parkin in non-small cell lung cancer.
OBJECTIVE
Parkin, a gene mutated in autosomal recessive juvenile Parkinsonism and mapped to the common fragile site FRA6E on human chromosome 6q25-q27, is associated with a frequent loss of heterozygosity and altered expression in breast and ovarian carcinomas. In addition, homozygous deletions of exon 2 creating deleterious truncations of the Parkin transcript were observed in the lung adenocarcinoma cell lines Calu-3 and H-1573, suggesting that the loss of this locus and the resulting changes in its expression are involved in the development of these tumors.


METHODS
We examined 20 paired normal and non-small cell lung cancer samples for the presence of Parkin alterations in the coding sequence and changes in gene expression. We also restored gene expression in the Parkin-deficient lung carcinoma cell line H460 by use of a recombinant lentivirus containing the wild-type Parkin cDNA.


RESULTS
Loss of heterozygosity analysis identified a common region of loss in the Parkin/FRA6E locus with the highest frequency for the intragenic marker D6S1599 (45%), and semi-quantitative reverse transcription-PCR revealed reduced expression in 3 of 9 (33%) lung tumors. Although we did not observe any in vitro changes in cell proliferation or cell cycle, ectopic Parkin expression had the ability to reduce in vivo tumorigenicity in nude mice.


CONCLUSIONS
These data suggest that Parkin is a tumor suppressor gene whose inactivation may play an important role in non-small cell lung cancer tumorigenesis.
Picchio
Maria Cristina
MC
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Martin
Eric Santos
ES
Cesari
Rossano
R
Calin
George Adrian
GA
Yendamuri
Sai
S
Kuroki
Tamotsu
T
Pentimalli
Francesca
F
Sarti
Manuela
M
Yoder
Kristine
K
Kaiser
Larry R
LR
Fishel
Richard
R
Croce
Carlo Maria
CM
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D005091:Exons; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006720:Homozygote; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D018895:Microsatellite Repeats; D008957:Models, Genetic; D009154:Mutation; D009368:Neoplasm Transplantation; D011110:Polymorphism, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000235:genetics*
D018076:DNA, Complementary; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein