Kansara Maya, Tsang Michael, Kodjabachian Laurent, Sims Natalie A, Trivett Melanie K, Ehrich Mathias, Dobrovic Alexander, Slavin John, Choong Peter F M, Simmons Paul J, Dawid Igor B, Thomas David M
Ian Potter Foundation Centre for Cancer Genetics and Preventative Medicine, and Sir Donald and Lady Trescowthick Laboratories, Peter MacCallumCancer Centre, Melbourne, Victoria, Australia.
J Clin Invest. 2009 Apr;119(4):837-51. doi: 10.1172/JCI37175. Epub 2009 Mar 23.
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 beta-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 beta-catenin levels, and increased proliferation. These data lead us to suggest that derepression of Wnt signaling by targeting secreted Wnt antagonists in osteoblasts may increase susceptibility to osteosarcoma.
Wnt信号通路通过刺激成骨细胞谱系的定向分化和增殖来增加骨量，这为正在研发的用于治疗骨质疏松症的新型促合成代谢治疗策略奠定了基础。这些策略包括通过靶向分泌型Wnt通路拮抗剂（如硬化蛋白）来解除对Wnt信号通路的抑制。然而，此类疗法存在安全隐患，即骨肉瘤（最常见的原发性骨恶性肿瘤）风险增加。在此，我们在一项高通量筛选中分析了5种人类骨肉瘤细胞系，以寻找表观遗传沉默的肿瘤抑制基因，并确定了Wnt抑制因子1（WIF1），它编码一种内源性分泌型Wnt通路拮抗剂，作为候选肿瘤抑制基因。在体外，WIF1可抑制人类骨肉瘤细胞系中的β-连环蛋白水平，诱导人和小鼠原代成骨细胞分化，并抑制小鼠和人类骨肉瘤细胞系的生长。Wif1在发育中的和成熟的小鼠骨骼中高表达，尽管它对正常发育并非必需，但靶向敲除小鼠Wif1会加速体内辐射诱导的骨肉瘤的发展。在原发性人类骨肉瘤中，启动子高甲基化导致WIF1沉默与分化丧失、β-连环蛋白水平升高以及增殖增加有关。这些数据使我们认为，通过靶向成骨细胞中的分泌型Wnt拮抗剂来解除对Wnt信号通路的抑制可能会增加患骨肉瘤的易感性。
