Hedgehog signaling induces osteosarcoma development through Yap1 and H19 overexpression
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AbstractOsteosarcoma 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.
All Author(s) ListChan LH, Wang W, Yeung W, Deng Y, Yuan P, Mak KK
Journal nameOncogene
Volume Number33
Issue Number40
PublisherNature Publishing Group: Open Access Hybrid Model Option B
Pages4857 - 4866
LanguagesEnglish-United Kingdom
Keywordslong non-coding RNA H19; osteosarcoma; yes-associated protein1
Web of Science Subject CategoriesBiochemistry & Molecular Biology; Cell Biology; Genetics & Heredity; Oncology

Last updated on 2020-06-07 at 01:08