Petrocca Fabio, Iliopoulos Dimitrios, Qin Haiyan R, Nicoloso Milena S, Yendamuri Say, Wojcik Sylwia E, Shimizu Masayoshi, Di Leva Gianpiero, Vecchione Andrea, Trapasso Francesco, Godwin Andrew K, Negrini Massimo, Calin George A, Croce Carlo M
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Cancer Res. 2006 Nov 1;66(21):10287-91. doi: 10.1158/0008-5472.CAN-06-2289.
ARLTS1 is a tumor suppressor gene initially described as a low-penetrance cancer gene: a truncated Trp149Stop (MUT) polymorphism is associated with general familial cancer aggregation and, particularly, high-risk familial breast cancer. DNA hypermethylation has been identified as a mechanism of ARLTS1 expression down-regulation in lung carcinomas and B-cell chronic lymphocytic leukemia. We found that, in the majority of ovarian carcinomas (61.5%) and in a significant proportion of ovarian and breast cancer cell lines (45%), ARLTS1 is strongly down-regulated due to DNA methylation in its promoter region. After ARLTS1 restoration by adenoviral transduction, only the negative TOV-112 and the homozygously mutated (MUT) MCF7 cells, but not the OV-90 cells expressing a normal ARLTS1 product, underwent apoptosis and inhibition of cell growth. Furthermore, ARLTS1 reexpression significantly reduced the tumorigenic potential of TOV-112 in nude mice. On the contrary, the ARLTS1-MUT induced significantly lower levels of apoptosis in infected cells and reduced in vivo tumorigenesis only partially, supporting the hypothesis that Trp149Stop polymorphism is retained in the general population and predisposes to cancer because of a reduction, but not full loss, of normal ARLTS1 function.
ARLTS1是一种肿瘤抑制基因，最初被描述为一种低外显率癌症基因：截短的Trp149Stop（MUT）多态性与一般家族性癌症聚集相关，尤其是与高危家族性乳腺癌相关。DNA高甲基化已被确定为肺癌和B细胞慢性淋巴细胞白血病中ARLTS1表达下调的一种机制。我们发现，在大多数卵巢癌（61.5%）以及相当比例的卵巢和乳腺癌细胞系（45%）中，ARLTS1因其启动子区域的DNA甲基化而强烈下调。通过腺病毒转导恢复ARLTS1后，只有阴性的TOV - 112细胞和纯合突变（MUT）的MCF7细胞，而不是表达正常ARLTS1产物的OV - 90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TOV - 112在裸鼠中的致瘤潜力。相反，ARLTS1 - MUT在感染细胞中诱导的凋亡水平显著较低，并且仅部分降低了体内肿瘤发生，这支持了这样一种假说，即Trp149Stop多态性在一般人群中保留，并且由于正常ARLTS1功能的降低而非完全丧失而导致易患癌症。
