MMSET Is Highly Expressed and Associated with Aggressiveness in Neuroblastoma
MMSET Is Highly Expressed and Associated with Aggressiveness in Neuroblastoma
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DOI：
10.1158/0008-5472.can-10-3810
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发表时间：
2011-06-15
期刊：
影响因子：
11.2
通讯作者：
Helin, Kristian
中科院分区：
文献类型：
--
作者：
Hudlebusch, Heidi Rye;Skotte, Julie;Helin, Kristian
MMSET（WHSC 1/NSD 2）是一种含有SET结构域的组蛋白赖氨酸甲基转移酶，其表达在具有与不良预后相关的t（4;14）（p16;q32）易位的多发性骨髓瘤亚组中失调。最近的研究表明，MMSET mRNA水平在其他肿瘤类型中也会增加。我们对组织芯片进行了免疫组化染色，发现MMSET蛋白在神经母细胞瘤中频繁且高度表达（75%的神经母细胞瘤中MMSET阳性，n = 164）。MMSET在神经母细胞瘤中的表达水平与不良生存率、阴性预后因素和转移性疾病显著相关。此外，化疗前和化疗后活检的神经母细胞瘤子集显示化疗后MMSET蛋白水平大幅下降。与神经母细胞瘤在治疗后变得更加分化一致，我们表明维甲酸诱导的体外人神经母细胞瘤细胞分化也导致MMSET水平的强烈下降。此外，我们表明，在正常神经祖细胞的高水平的MMSET强烈下调分化过程中。重要的是，我们发现MMSET是神经母细胞瘤细胞和脑源性神经干细胞增殖所必需的。两者合计，我们的研究结果表明，MMSET可能通过支持祖细胞的增殖和负调控其分化而参与神经母细胞瘤的发生。在这方面，MMSET可能是一个强大的候选治疗靶点，在一个子集的神经母细胞瘤预后不良。Cancer Res; 71（12）; 4226-35.（C）2011年《非洲标准化评论》。
MMSET (WHSC1/NSD2) is a SET domain-containing histone lysine methyltransferase the expression of which is deregulated in a subgroup of multiple myelomas with the t(4;14)(p16;q32) translocation associated with poor prognosis. Recent studies have shown that MMSET mRNA levels are increased in other tumor types as well. We have carried out immunohistochemical staining of tissue microarrays and found that MMSET protein is frequently and highly expressed in neuroblastoma (MMSET positive in 75% of neuroblastomas, n = 164). The expression level of MMSET in neuroblastomas was significantly associated with poor survival, negative prognostic factors, and metastatic disease. Moreover, a subset of neuroblastomas for which pre- and post-chemotherapy biopsies were available displayed a strong decrease in MMSET protein levels after chemotherapy. In agreement with neuroblastomas becoming more differentiated after treatment, we show that retinoic acid-induced differentiation of human neuroblastoma cells in vitro also leads to a strong decrease in MMSET levels. Furthermore, we show that the high levels of MMSET in normal neural progenitor cells are strongly down-regulated during differentiation. Importantly, we show that MMSET is required for proliferation of neuroblastoma cells and brain-derived neural stem cells. Taken together, our results suggest that MMSET is implicated in neuroblastomagenesis possibly by supporting proliferation of progenitor cells and negatively regulating their differentiation. In this respect, MMSET might be a strong candidate therapeutic target in a subset of neuroblastomas with unfavorable prognosis. Cancer Res; 71(12); 4226-35. (C)2011 AACR.