Gozo Maricel C, Jia Dongyu, Aspuria Paul-Joseph, Cheon Dong-Joo, Miura Naoyuki, Walts Ann E, Karlan Beth Y, Orsulic Sandra
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Graduate Program in Biomedical Science and Translational Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Oncotarget. 2016 Oct 18;7(42):68792-68802. doi: 10.18632/oncotarget.11990.
Osteosarcoma is a highly malignant tumor that contains a small subpopulation of tumor-propagating cells (also known as tumor-initiating cells) characterized by drug resistance and high metastatic potential. The molecular mechanism by which tumor-propagating cells promote tumor growth is poorly understood. Here, we report that the transcription factor forkhead box C2 (FOXC2) is frequently expressed in human osteosarcomas and is important in maintaining osteosarcoma cells in a stem-like state. In osteosarcoma cell lines, we show that anoikis conditions stimulate FOXC2 expression. Downregulation of FOXC2 decreases anchorage-independent growth and invasion in vitro and lung metastasis in vivo, while overexpression of FOXC2 increases tumor propagation in vivo. In osteosarcoma cell lines, we demonstrate that high levels of FOXC2 are associated with and required for the expression of osteosarcoma tumor-propagating cell markers. In FOXC2 knockdown cell lines, we show that CXCR4, a downstream target of FOXC2, can restore osteosarcoma cell invasiveness and metastasis to the lung.
骨肉瘤是一种高度恶性的肿瘤，其中包含一小部分具有耐药性和高转移潜能的肿瘤增殖细胞（也称为肿瘤起始细胞）。肿瘤增殖细胞促进肿瘤生长的分子机制目前尚不清楚。在此，我们报告转录因子叉头框C2（FOXC2）在人类骨肉瘤中经常表达，并且在维持骨肉瘤细胞处于干细胞样状态方面发挥重要作用。在骨肉瘤细胞系中，我们发现失巢凋亡条件会刺激FOXC2表达。FOXC2的下调会降低体外非锚定依赖性生长和侵袭以及体内肺转移，而FOXC2的过表达会增加体内肿瘤增殖。在骨肉瘤细胞系中，我们证明高水平的FOXC2与骨肉瘤肿瘤增殖细胞标志物的表达相关且是其表达所必需的。在FOXC2敲低的细胞系中，我们发现FOXC2的下游靶点CXCR4可以恢复骨肉瘤细胞的侵袭性和肺转移能力。
