PMID- 24141783
OWN - NLM
STAT- MEDLINE
DCOM- 20141126
LR  - 20220204
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 33
IP  - 40
DP  - 2014 Oct 2
TI  - Hedgehog signaling induces osteosarcoma development through Yap1 and H19 
      overexpression.
PG  - 4857-66
LID - 10.1038/onc.2013.433 [doi]
AB  - 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.
FAU - Chan, L H
AU  - Chan LH
AD  - 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.
FAU - Wang, W
AU  - Wang W
AD  - 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.
FAU - Yeung, W
AU  - Yeung W
AD  - 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.
FAU - Deng, Y
AU  - Deng Y
AD  - 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.
FAU - Yuan, P
AU  - Yuan P
AD  - Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong 
      SAR.
FAU - Mak, K K
AU  - Mak KK
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131021
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (H19 long non-coding RNA)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Phosphoproteins)
RN  - 0 (RNA, Long Noncoding)
RN  - 0 (YAP-Signaling Proteins)
RN  - 0 (Yap1 protein, mouse)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/genetics/*metabolism
MH  - Animals
MH  - Bone Neoplasms/*metabolism/pathology
MH  - Carcinogenesis
MH  - Cell Cycle Proteins
MH  - Gene Expression
MH  - Hedgehog Proteins/*metabolism
MH  - Mice, 129 Strain
MH  - Mice, Inbred C57BL
MH  - Mice, Nude
MH  - Neoplasm Transplantation
MH  - Osteosarcoma/*metabolism/pathology
MH  - Phosphoproteins/genetics/*metabolism
MH  - RNA, Long Noncoding/genetics/*metabolism
MH  - Signal Transduction
MH  - Tumor Cells, Cultured
MH  - YAP-Signaling Proteins
EDAT- 2013/10/22 06:00
MHDA- 2014/12/15 06:00
CRDT- 2013/10/22 06:00
PHST- 2013/07/24 00:00 [received]
PHST- 2013/09/06 00:00 [revised]
PHST- 2013/09/13 00:00 [accepted]
PHST- 2013/10/22 06:00 [entrez]
PHST- 2013/10/22 06:00 [pubmed]
PHST- 2014/12/15 06:00 [medline]
AID - onc2013433 [pii]
AID - 10.1038/onc.2013.433 [doi]
PST - ppublish
SO  - Oncogene. 2014 Oct 2;33(40):4857-66. doi: 10.1038/onc.2013.433. Epub 2013 Oct 21.