Guan H, Tan P, Xie L, Mi B, Fang Z, Li J, Yue J, Liao H, Li F
Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cancer Center of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Oncogenesis. 2015 Sep 7;4(9):e166. doi: 10.1038/oncsis.2015.25.
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.
近期的研究进展突显了FOXO转录因子，尤其是FOXO1，在骨骼发育和重塑中的重要作用。FOXOs对骨骼发育的调控似乎具有阶段特异性或依赖于具体环境。FOXOs促进成骨细胞谱系早期祖细胞的维持和分化，并抑制定向成骨细胞前体的增殖；FOXO1对骨细胞存活至关重要。鉴于FOXOs在骨骼发育和肿瘤发生中发挥的多种作用，骨中起非冗余作用的主要FOXO1可能对骨肉瘤（OS）的发生有影响，这是合理的。事实上，最近的研究结果表明FOXO1在骨肉瘤中具有肿瘤抑制作用。在本研究中，我们发现FOXO1在骨肉瘤中的表达通常较低或缺失，少数病例有中度表达。全基因组测序（WGS）显示，FOXO1基因座在骨肉瘤中经常发生拷贝数变异和杂合性缺失，表明染色体畸变可能部分导致了FOXO1表达的异质性。在骨肉瘤细胞系中激活FOXO1可抑制癌细胞存活，这可归因于对包括BIM在内的靶基因的调控以及对Wnt/β-连环蛋白信号通路的抑制。抑制FOXO1可促进骨肉瘤细胞系的细胞增殖、增强集落形成并减弱其成骨分化。总之，我们的结果证明FOXO1至少部分通过抑制Wnt/β-连环蛋白通路在骨肉瘤中作为肿瘤抑制因子发挥作用。
