Tumor suppressor functions of ARLTS1 in lung cancers.
ARLTS1 is a newly characterized tumor suppressor gene located at chromosome 13q14.3 and involved in the pathogenesis of various types of tumors: two single-nucleotide polymorphisms, one of them responsible for protein truncation, were found statistically associated with familial malignancies, whereas DNA hypermethylation and genomic deletions have been identified as a mechanism of ARLTS1 down-regulation in sporadic cancers. We found that in a large portion of lung carcinomas (37%) and in all analyzed lung cancer cell lines, ARLTS1 is strongly down-regulated due to DNA methylation in its promoter region. After its restoration by adenoviral transduction, ARLTS1-negative A549 and H1299 cells underwent apoptosis and inhibition of cell growth. Furthermore, ARLTS1 reexpression significantly reduced the ability of A549 and H1299 to form tumors in nude mice. Finally, we identified approximately 650 transcripts differentially expressed after restoration of ARLTS1 expression in A549 cells, suggesting that various pathways involved in cell survival, proliferation, signaling, and development mediate the effects of wild-type ARLTS1 in a lung cancer system.
Yendamuri
Sai
S
Kimmel Cancer Center, Thomas Jefferson University, PA, USA.
Trapasso
Francesco
F
Ferracin
Manuela
M
Cesari
Rossano
R
Sevignani
Cinzia
C
Shimizu
Masayoshi
M
Rattan
Shashi
S
Kuroki
Tamotsu
T
Dumon
Kristoffel R
KR
Bullrich
Florencia
F
Liu
Chang-gong
CG
Negrini
Massimo
M
Williams
Noel N
NN
Kaiser
Larry R
LR
Croce
Carlo M
CM
Calin
George A
GA
D020727:ADP-Ribosylation Factors / Q000096:biosynthesis / Q000235:genetics*; D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D019175:DNA Methylation; D015536:Down-Regulation; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D016415:Sequence Alignment
D020727:ADP-Ribosylation Factors; C500039:ARL11 protein, human