期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 47, 页码 E11128-E11137出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1814044115
关键词
SFRP2; p53; osteosarcoma; autocrine; paracrine
资金
- Graduate School of Biomedical Sciences at the Icahn School of Medicine at Mount Sinai
- National Cancer Institute [1F99CA212489]
- NIH Pathway to Independence Award [R00CA181496]
- NIH Cancer Prevention Research Institute of Texas Award [RR160019]
- Empire State Stem Cell Fund through the New York State Department of Health [C024410]
- NIH [5R01GM078465]
- NATIONAL CANCER INSTITUTE [F99CA212489, R00CA181496] Funding Source: NIH RePORTER
Osteosarcoma (OS), the most common primary bone tumor, is highly metastatic with high chemotherapeutic resistance and poor survival rates. Using induced pluripotent stem cells (iPSCs) generated from Li-Fraumeni syndrome (LFS) patients, we investigate an oncogenic role of secreted frizzled-related protein 2 (SFRP2) in p53 mutation-associated OS development. Interestingly, we find that high SFRP2 expression in OS patient samples correlates with poor survival. Systems-level analyses identified that expression of SFRP2 increases during LFS OS development and can induce angiogenesis. Ectopic SFRP2 overexpression in normal osteoblast precursors is sufficient to suppress normal osteoblast differentiation and to promote OS phenotypes through induction of oncogenic molecules such as FOXM1 and CYR61 in a beta-catenin-independent manner. Conversely, inhibition of SFRP2, FOXM1, or CYR61 represses the tumorigenic potential. In summary, these findings demonstrate the oncogenic role of SFRP2 in the development of p53 mutation-associated OS and that inhibition of SFRP2 is a potential therapeutic strategy.
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