FOXO1 inhibits osteosarcoma oncogenesis via Wnt/β-catenin pathway suppression.
FOXO1 inhibits osteosarcoma oncogenesis via Wnt/β-catenin pathway suppression.
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DOI：
10.1038/oncsis.2015.25
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发表时间：
2015-09-07
期刊：
影响因子：
6.2
通讯作者：
Li F
中科院分区：
文献类型：
--
作者：
Guan H;Tan P;Xie L;Mi B;Fang Z;Li J;Yue J;Liao H;Li F
近年来的研究进展强调了FOXO转录因子，特别是fox01在骨骼发育和重塑中的重要作用。FOXOs对骨发育的调控似乎是阶段特异性或环境依赖性的。FOXOs促进成骨细胞谱系早期祖细胞的维持和分化，抑制成骨细胞前体的增殖；fox01对骨细胞的存活至关重要。考虑到FOXO在骨发育和肿瘤发生中发挥的多种作用，fox01作为骨中主要的FOXO具有非冗余作用，可能对骨肉瘤（OS）的肿瘤发生有影响。事实上，最近的研究结果表明fox01在OS中具有肿瘤抑制作用。在本研究中，我们发现FOXO1在OS中普遍低表达或不表达，少数病例有中等表达。全基因组测序（WGS）显示FOXO1位点在OS中经常参与拷贝数变异和杂合性缺失，提示染色体畸变可能是FOXO1表达异质性的部分原因。FOXO1在OS细胞系中的激活抑制了癌细胞的存活，这可以归因于靶基因的调节，包括BIM和抑制Wnt/β-catenin信号传导。FOXO1抑制可促进骨肉瘤细胞系细胞增殖，增强集落形成，减弱成骨分化。总之，我们的研究结果证明FOXO1在OS中至少部分是通过抑制Wnt/β-catenin通路来抑制肿瘤的。
Recent advances have highlighted profound roles of FOXO transcription factors, especially FOXO1, in bone development and remodeling. The regulation of bone development by FOXOs seems to be stage-specific or context dependent. FOXOs promote maintenance and differentiation of early progenitors of the osteoblast lineage and repress proliferation of committed osteoblast precursors; FOXO1 is vital for osteocyte survival. Considering the versatile roles played by FOXOs in bone development and tumorigenesis, it is plausible that FOXO1, the main FOXO in bone with a non-redundant role, might have influence on osteosarcoma (OS) oncogenesis. Indeed, recent results have implicated that FOXO1 has a tumor-suppressing role in OS. In the present study, we found that FOXO1 expression was generally low or absent in OS, with a minority of cases having moderate expression. Whole-genome sequencing (WGS) revealed that the FOXO1 locus was frequently involved in copy number variation and loss of heterozygosity in OS, indicating that chromosomal aberrations might be partially responsible for the heterogeneity in FOXO1 expression. FOXO1 activation in OS cell lines inhibited cancer cell survival, which can be attributed to modulation of target genes, including BIM and repressed Wnt/β-catenin signaling. FOXO1 inhibition promoted cell proliferation, enhanced colony formation and attenuated osteogenic differentiation of OS cell lines. To conclude, our results proved FOXO1 as a tumor suppressor in OS at least partially by suppression of the Wnt/β-catenin pathway.