Casola S, Pedone P V, Cavazzana A O, Basso G, Luksch R, d'Amore E S, Carli M, Bruni C B, Riccio A
Centro di Endocrinologia ed Oncologia Sperimentale, CNR, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Naples, Italy.
Oncogene. 1997 Mar 27;14(12):1503-10. doi: 10.1038/sj.onc.1200956.
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.
胰岛素样生长因子2（IGF-2）和H19这两个基因位于人类11号染色体p15区域，具有细胞生长调节活性，其表达受亲本印记调控，即它们的等位基因活性取决于亲本来源。在几种儿童癌症中观察到的11号染色体p15区域遗传改变中的亲本偏向性表明印记基因参与了肿瘤发生。我们之前报道过，由于印记放松（LOI）或基因复制，横纹肌肉瘤（RMS）中功能性IGF-2等位基因的数量经常增加。在此我们表明，在15例胚胎组织学类型的横纹肌肉瘤（ERMS）中有13例以及在11例被归类为肺泡亚型的横纹肌肉瘤（ARMS）中有3例，相对于正常肌肉组织，H19基因的表达显著受到抑制。由于已发现H19基因具有生长抑制活性，其表达的缺失可能促成了RMS的发生。在所有信息充分的RMS中，包括那些IGF-2印记放松的病例，均发现H19基因的亲本印记是保守的，这表明LOI是一个基因特异性事件。7例ERMS和1例ARMS的H19 RNA水平较低，其基因型中表达的等位基因出现频率较低。这一结果与H19基因的父本印记以及这些肿瘤中母本11号染色体p15等位基因的优先丢失是一致的。在8例11号染色体p15保持杂合性但显示IGF-2 LOI的RMS中，也有4例发现H19表达较低。这些发现表明，大量RMS中影响11号染色体p15的遗传和表观遗传改变导致不止一个印记基因失调，可能影响肿瘤生长，包括H19表达的缺失和活性IGF-2等位基因数量的增加。
