Hedgehog signaling induces osteosarcoma development through Yap1 and H19 overexpression
Hedgehog signaling induces osteosarcoma development through Yap1 and H19 overexpression
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DOI：
10.1038/onc.2013.433
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发表时间：
2014-10-02
期刊：
影响因子：
8
通讯作者：
Mak, K. K.
中科院分区：
文献类型：
--
作者：
Chan, L. H.;Wang, W.;Mak, K. K.
骨肉瘤是最常见的骨肿瘤之一。然而，其发病的遗传学基础仍不清楚。在这里，我们研究了Hedgehog(HH)信号在骨肉瘤发展中的作用。在成熟的成骨细胞中普遍存在HH信号上调的基因工程小鼠会出现局灶性骨过度生长，这与骨肉瘤的早期非常相似。然而，这些小鼠在三个月内死亡，这阻碍了对肿瘤进展的进一步分析。因此，我们建立了一个在成熟成骨细胞中部分上调HH信号的小鼠模型，并将其交叉到p53杂合背景中，以促进肿瘤的发展。我们发现这些突变的小鼠发生了高外显性的恶性骨肉瘤。分离的原代肿瘤细胞主要为成骨细胞，高度增殖，具有许多人骨肉瘤的特征。免疫低下小鼠的同种异体移植显示出很高的致瘤潜力。更重要的是，人类和小鼠的肿瘤组织都表达高水平的YAP1，这是一种在各种癌症中被放大的有效癌基因。我们发现抑制HH信号减少了YAP1的表达，并且YAP1的敲除显著地抑制了肿瘤的进展。此外，HH信号上调和YAP1过表达诱导了长非编码RNA H19的异常表达。我们的结果表明，成熟成骨细胞中异常的HH信号是通过YAP1和H19过表达而导致骨肉瘤发生的。
Osteosarcoma is one of the most common bone tumors. However, the genetic basis for its pathogenesis remains elusive. Here, we investigated the roles of Hedgehog (Hh) signaling in osteosarcoma development. Genetically-engineered mice with ubiquitous upregulated Hh signaling specifically in mature osteoblasts develop focal bone overgrowth, which greatly resembles the early stage of osteosarcoma. However, these mice die within three months, which prohibits further analysis of tumor progression. We therefore generated a mouse model with partial upregulated Hh signaling in mature osteoblasts and crossed it into a p53 heterozygous background to potentiate tumor development. We found that these mutant mice developed malignant osteosarcoma with high penetrance. Isolated primary tumor cells were mainly osteoblastic and highly proliferative with many characteristics of human osteosarcomas. Allograft transplantation into immunocompromised mice displayed high tumorigenic potential. More importantly, both human and mouse tumor tissues express high level of yes-associated protein 1 (Yap1), a potent oncogene that is amplified in various cancers. We show that inhibition of Hh signaling reduces Yap1 expression and knockdown of Yap1 significantly inhibits tumor progression. Moreover, long non-coding RNA H19 is aberrantly expressed and induced by upregulated Hh signaling and Yap1 overexpression. Our results demonstrate that aberrant Hh signaling in mature osteoblasts is responsible for the pathogenesis of osteoblastic osteosarcoma through Yap1 and H19 overexpression.