Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice
Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice
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DOI：
10.1172/jci37175
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发表时间：
2009-04-01
影响因子：
15.9
通讯作者：
Thomas, David M.
中科院分区：
文献类型：
--
作者：
Kansara, Maya;Tsang, Michael;Thomas, David M.
WNT信号通过刺激成骨细胞的承接和扩张来增加骨量，并形成了正在开发的治疗骨质疏松的新的合成代谢治疗策略的基础。这些策略包括通过靶向分泌的Wnt途径拮抗剂，如硬化素，来解除Wnt信号的抑制。然而，这样的治疗与增加骨肉瘤风险的安全担忧有关，骨肉瘤是最常见的原发骨恶性肿瘤。在这里，我们在高通量筛选中分析了5个人骨肉瘤细胞系，以寻找表观遗传沉默的肿瘤抑制基因，并确定编码内源性分泌的Wnt途径拮抗剂的Wnt抑制因子1(WIF1)是一个候选的肿瘤抑制基因。在体外，WIF1抑制人骨肉瘤细胞株中P-catenin的水平，诱导人和小鼠原代成骨细胞分化，并抑制小鼠和人骨肉瘤的生长。细胞线。Wif1在发育和成熟的小鼠骨骼中高度表达，尽管它对正常发育是必不可少的，但靶向缺失小鼠Wif1加速了体内辐射诱导的骨肉瘤的发展。在原发的人类骨肉瘤中，启动子高甲基化导致WIF1的沉默与分化丧失、P-连环蛋白水平升高和增殖增加相关。这些数据使我们认为，通过靶向成骨细胞中分泌的Wnt拮抗剂来抑制WRIT信号可能会增加骨肉瘤的易感性。
Wnt signaling increases bone mass by stimulating osteoblast lineage commitment and expansion and forms the basis for novel anabolic therapeutic strategies being developed for osteoporosis. These strategies include derepression of Wnt signaling by targeting secreted Wnt pathway antagonists, such as sclerostin. However, such therapies are associated with safety concerns regarding an increased risk of osteosarcoma, the most common primary malignancy of bone. Here, we analyzed 5 human osteosarcoma cell lines in a high-throughput screen for epigenetically silenced tumor suppressor genes and identified Wnt inhibitory factor 1 (WIF1), which encodes an endogenous secreted Wnt pathway antagonist, as a candidate tumor suppressor gene. In vitro, WIF1 suppressed P-catenin levels in human osteosarcoma cell lines, induced differentiation of human and mouse primary osteoblasts, and suppressed the growth of mouse and human osteosarcoma. cell Lines. Wif1 was highly expressed in the developing and mature mouse skeleton, and, although it was dispensable for normal development, targeted deletion of mouse Wif1 accelerated development of radiation-induced osteosarcomas in vivo. In primary human osteosarcomas, silencing of WIF1 by promoter hypermethylation was associated with loss of differentiation, increased P-catenin levels, and increased proliferation. These data lead us to suggest that derepression of Writ signaling by targeting secreted Wnt antagonists in osteoblasts may increase susceptibility to osteosarcoma.