High expression of CAI2, a 9p21-embedded long noncoding RNA, contributes to advanced-stage neuroblastoma.
High expression of CAI2, a 9p21-embedded long noncoding RNA, contributes to advanced-stage neuroblastoma.
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DOI：
10.1158/0008-5472.can-13-3447
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发表时间：
2014-07-15
期刊：
影响因子：
11.2
通讯作者：
Diccianni MB
中科院分区：
文献类型：
--
作者：
Barnhill LM;Williams RT;Cohen O;Kim Y;Batova A;Mielke JA;Messer K;Pu M;Bao L;Yu AL;Diccianni MB
神经母细胞瘤是一种具有显著基因组和生物学异质性的儿科癌症。p16和ARF是染色体9 p21上两个重要的肿瘤抑制基因，在大多数癌症中通常是失活的，但在神经母细胞瘤中却反常地过表达。在这里，我们报告，外显子γ在p16也是一个未知的长非编码RNA（lncRNA），我们称之为CAI 2（CDKN 2A/ARF内含子2 lncRNA）的一部分。CAI 2是一个位于p16/ARF外显子3中但独立于p16/ARF外显子3的单外显子基因，具有多聚A信号。CAI 2在正常组织中以非常低的水平表达，但在具有完整9 p21基因座的大多数肿瘤细胞系中高度表达。在正常组织中CAI 2与p16和ARF的一致表达沿着CAI 2诱导p16表达的能力表明CAI 2可能调节p16和/或ARF。在体外连续传代转化的神经母细胞瘤细胞中，CAI 2、p16和ARF的表达均显著增加，导致细胞增殖更快。在原发性神经母细胞瘤中也观察到类似的关系，其中CAI 2表达在晚期神经母细胞瘤中显著更高，独立于MYCN扩增。与其与高风险疾病的相关性一致，CAI 2表达也与不良临床结局显著相关，尽管当调整MYCN扩增时，这种影响降低。总之，我们的研究结果表明，CAI 2有助于神经母细胞瘤中p16的反常过表达，其中CAI 2可能提供一个有用的高风险疾病的生物标志物。
Neuroblastoma is a pediatric cancer with significant genomic and biological heterogeneity. p16 and ARF, two important tumor suppressor genes on chromosome 9p21, are inactivated commonly in most cancers but paradoxically overexpressed in neuroblastoma. Here we report that exon γ in p16 is also part of an undescribed long non-coding RNA (lncRNA) that we have termed CAI2 (CDKN2A/ARF Intron 2 lncRNA). CAI2 is a single exon gene with a poly A signal located in but independent of the p16/ARF exon 3. CAI2 is expressed at very low levels in normal tissue but is highly expressed in most tumor cell lines with an intact 9p21 locus. Concordant expression of CAI2 with p16 and ARF in normal tissue along with the ability of CAI2 to induce p16 expression suggested that CAI2 may regulate p16 and/or ARF. In neuroblastoma cells transformed by serial passage in vitro, leading to more rapid proliferation, CAI2, p16 and ARF expression all increased dramatically. A similar relationship was also observed in primary neuroblastomas where CAI2 expression was significantly higher in advanced stage neuroblastoma, independently of MYCN amplification. Consistent with its association with high risk disease, CAI2 expression was also significantly associated with poor clinical outcomes, although this effect was reduced when adjusted for MYCN amplification. Taken together, our findings suggested that CAI2 contributes to the paradoxical overexpression of p16 in neuroblastoma, where CAI2 may offer a useful biomarker of high-risk disease.