Expression and parental imprinting of the H19 gene in human rhabdomyosarcoma.
The expression of Insulin-like Growth Factor 2 (IGF-2) and H19, two genes located on human chromosome 11p15 and provided with cell growth modulating activity, is regulated by parental imprinting, in that the activity of their alleles is dependent on the parental origin. Parental bias in the genetic alterations of chromosome 11p15 observed in several pediatric cancers suggests the involvement of imprinted genes in tumor development. We have previously reported that the number of functional IGF-2 alleles is frequently increased in rhabdomyosarcoma (RMS), as a consequence of either relaxation of imprinting (LOI) or gene duplication. Here we show that the expression of the H19 gene is significantly suppressed with respect to normal muscle tissue in 13 out of 15 rhabdomyosarcomas with embryonal histology (ERMS) and in three out of 11 rhabdomyosarcomas classified as alveolar subtype (ARMS). Since a growth-inhibitory activity has been found associated with the H19 gene, the extinction of its expression can contribute to RMS development. Parental imprinting of the H19 gene was found conserved in all informative RMSs, including those whose ICF-2 imprinting was relaxed, indicating that LOI is a gene-specific event. Seven ERMSs and one ARMS displaying low H19 RNA levels showed an underrepresentation of the expressed allele in their genotype. This result is consistent with the paternal imprinting of the H19 gene and with the preferential loss of the maternal 11p15 alleles in these neoplasms. Low H19 expression was also found in four out of eight RMSs retaining the heterozygosity at 11p15, but showing IGF-2 LOI. These findings suggest that the genetic and epigenetic alterations affecting chromosome 11p15 in a high number of RMSs cause deregulation of more than one imprinted gene, possibly affecting tumor growth, including the extinction of H19 expression and an increase in the number of active IGF-2 alleles.
Casola
S
S
Centro di Endocrinologia ed Oncologia Sperimentale, CNR, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Naples, Italy.
Pedone
P V
PV
Cavazzana
A O
AO
Basso
G
G
Luksch
R
R
d'Amore
E S
ES
Carli
M
M
Bruni
C B
CB
Riccio
A
A
D000483:Alleles; D004268:DNA-Binding Proteins / Q000235:genetics; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D006579:Heterozygote; D018398:Homeodomain Proteins; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D019042:Muscle Neoplasms / Q000235:genetics* / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics*; D009132:Muscles / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics; D000072041:PAX3 Transcription Factor; D051763:PAX7 Transcription Factor; D051761:Paired Box Transcription Factors; D062085:RNA, Long Noncoding; D012333:RNA, Messenger / Q000235:genetics; D022661:RNA, Untranslated; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics; D014178:Translocation, Genetic
D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C094335:H19 long non-coding RNA; D018398:Homeodomain Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051763:PAX7 Transcription Factor; D051761:Paired Box Transcription Factors; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D022661:RNA, Untranslated; D014157:Transcription Factors; C068686:Pax3 protein, mouse; D007335:Insulin-Like Growth Factor II