Yendamuri Sai, Trapasso Francesco, Ferracin Manuela, Cesari Rossano, Sevignani Cinzia, Shimizu Masayoshi, Rattan Shashi, Kuroki Tamotsu, Dumon Kristoffel R, Bullrich Florencia, Liu Chang-gong, Negrini Massimo, Williams Noel N, Kaiser Larry R, Croce Carlo M, Calin George A
Kimmel Cancer Center, Thomas Jefferson University, PA, USA.
Cancer Res. 2007 Aug 15;67(16):7738-45. doi: 10.1158/0008-5472.CAN-07-1481.
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.
ARLTS1是一个新发现的肿瘤抑制基因，位于染色体13q14.3，参与多种类型肿瘤的发病机制：发现两个单核苷酸多态性，其中一个导致蛋白质截短，与家族性恶性肿瘤存在统计学关联，而DNA高甲基化和基因组缺失已被确定为散发性癌症中ARLTS1下调的机制。我们发现，在大部分肺癌（37%）以及所有分析的肺癌细胞系中，由于其启动子区域的DNA甲基化，ARLTS1被强烈下调。通过腺病毒转导恢复其表达后，ARLTS1阴性的A549和H1299细胞发生凋亡并抑制细胞生长。此外，ARLTS1的重新表达显著降低了A549和H1299在裸鼠体内形成肿瘤的能力。最后，我们鉴定出在A549细胞中恢复ARLTS1表达后约650个差异表达的转录本，这表明参与细胞存活、增殖、信号传导和发育的各种途径介导了野生型ARLTS1在肺癌系统中的作用。
