title: Hedgehog signaling induces osteosarcoma development through Yap1 and H19 overexpression.
abstract: 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.
authors.affiliation: Key Laboratories for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR.
authors.forename: L H
authors.initials: LH
authors.lastname: Chan
authors.affiliation: Key Laboratories for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR.
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.affiliation: Key Laboratories for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR.
authors.forename: W
authors.initials: W
authors.lastname: Yeung
authors.affiliation: Key Laboratories for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR.
authors.forename: Y
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: P
authors.initials: P
authors.lastname: Yuan
authors.affiliation: 1] Key Laboratories for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR [2] Stem Cell and Regeneration Thematic Research Program, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR [3] CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
authors.forename: K K
authors.initials: KK
authors.lastname: Mak
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D063646:Carcinogenesis; D018797:Cell Cycle Proteins; D015870:Gene Expression; D053823:Hedgehog Proteins / Q000378:metabolism*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C094335:H19 long non-coding RNA; D053823:Hedgehog Proteins; D010750:Phosphoproteins; D062085:RNA, Long Noncoding; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse