Oncogenic role of sFRP2 in P53-mutant osteosarcoma development via autocrine and paracrine mechanism
| Autor: | Dung Fang Lee, Ye Yuan, Jeffrey M. Bernitz, Seungyeul Yoo, Kateri A. Moore, Elizabeth G. Demicco, Andreia Gomes, Jie Su, Huen Suk Kim, Michael G. Daniel, Christoph Schaniel, Ihor R. Lemischka, Jun Zhu |
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| Rok vydání: | 2018 |
| Předmět: |
0303 health sciences
Angiogenesis Osteoblast Biology medicine.disease Phenotype 3. Good health 03 medical and health sciences 0302 clinical medicine medicine.anatomical_structure 030220 oncology & carcinogenesis CYR61 medicine FOXM1 Cancer research Osteosarcoma Autocrine signalling Induced pluripotent stem cell 030304 developmental biology |
| DOI: | 10.1101/246454 |
| Popis: | 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 investigated an oncogenic role of secreted frizzled-related protein 2 (sFRP2) in P53 mutation-associated OS development. Interestingly, we found 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 β-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 P53 mutation-associated OS development and that inhibition of sFRP2 is a potential therapeutic strategy. |
| Databáze: | OpenAIRE |
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