HACE1 Is a Tumor Suppressor Gene Candidate in Natural Killer Cell Neoplasms
HACE1 Is a Tumor Suppressor Gene Candidate in Natural Killer Cell Neoplasms
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DOI：
10.1016/j.ajpath.2012.09.012
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发表时间：
2013-01-01
影响因子：
6
通讯作者：
Chan, Wing C.
中科院分区：
文献类型：
--
作者：
Kuecuek, Can;Hu, Xiaozhou;Chan, Wing C.
HACE 1是位于6 q21的E3泛素连接酶，6 q21是自然杀伤（NK）细胞恶性肿瘤中经常缺失的基因组区域。在这里，我们报告作为一个候选的肿瘤抑制基因沉默通过组合的缺失和胞嘧啶磷酸鸟嘌呤岛甲基化。我们通过定量PCR在恶性NK细胞系（6/9，67%）和原发性活检组织（5/15，33%）中检测到HACE 1缺失，大多数标本显示剩余等位基因中的胞嘧啶磷酸鸟嘌呤岛高甲基化，导致低mRNA转录。在一个不含HACE 1的NK细胞系中，HACE 1的异位表达导致细胞凋亡和G（2）/M周期阻滞。此外，在IL-2激活的正常NK细胞和与工程NK细胞靶点K562克隆9.mbIL21共培养的NK细胞中，HACE 1表达上调，表明其在调节NK细胞稳态中发挥作用。结论：HACE 1是位于6 q21区域内的另一个有效的肿瘤抑制基因，6 q21区域内多个肿瘤抑制基因的功能丧失可能是NK细胞淋巴瘤发生的关键决定因素。(Am J Pathol 2013，182：49-55; http：//dx·doi·org/10·1016/j·ajpath·2012·09·012）
HACE1 is an E3 ubiquitin ligase located in 6q21, the genomic region frequently deleted in natural killer (NK) cell malignancies. Here, we report HACE1 as a candidate tumor suppressor gene silenced through a combination of deletion and cytosine phosphate guanine island hypermethylation. We detected deletion of HACE1 in malignant NK cell lines (6 of 9, 67%) and primary biopsies (5 of 15, 33%) by quantitative PCR, with most of the specimen showing cytosine phosphate guanine island hypermethylation in the remaining allele, Leading to Low mRNA transcription. The ectopic expression of HACE1 in an HACE1-null NK cell Line led to apoptosis and G(2)/M cell cycle arrest. Moreover, HACE1 expression was up-regulated in IL-2-activated normal NK cells and NK cells cocultured with an engineered NK cell target, K562 Clone 9.mbIL21, suggesting its rote in the regulation of NK cell homeostasis. In conclusion, HACE1 is another potent tumor suppressor gene located within the 6q21 region, and loss of function of multiple tumor suppressor genes within 6q21 may be a critical determinant of NK cell Lymphomagenesis. (Am J Pathol 2013, 182: 49-55; http://dx.doi.org/10.1016/j.ajpath.2012.09.012)