Tong Ziyuan, Shen Yuan, Yuan Quan, Yu Honghao
Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, People's Republic of China.
Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, People's Republic of China.
Biochim Biophys Acta Mol Cell Res. 2023 Oct;1870(7):119553. doi: 10.1016/j.bbamcr.2023.119553. Epub 2023 Jul 30.
Despite recent advances in understanding the biological behavior of osteosarcoma (OS), OS is still the most common primary bone sarcoma that endangers the health of children and adolescents. High-temperature requirement A (HTRA) protease family plays an important regulatory role in numerous malignancies and acts as a prognostic biomarker. However, the function and underlying mechanisms of the HTRA family in OS development remain unknown. Through analyzing the GSE126209 dataset obtained from different Gene Expression Omnibus (GEO) databases, we found that HTRA3 as a member of the HTRA family was downregulated in OS tissues compared with that in normal tissues. Functional experiments indicated that HTRA3 overexpression suppressed malignant behaviors of OS cells in vitro and tumor growth in vivo. Mechanistically, we found that HTRA3 co-localized with the X-linked inhibitor of apoptosis protein (XIAP) and decreased XIAP stability. Further investigation showed that XIAP knockdown inhibited the degradation of phosphatase and tensin homolog (PTEN) and that HTRA3 caused the blockage of PTEN/phosphoinositide 3-kinase (PI3K)/AKT pathway, characterized as the reverse of cell function caused by HTRA3 overexpression after PTEN inhibitor BpV (HOpic) treatment. Detailed investigations showed that forkhead box protein 1 (FOXP1), an oncogene in OS progression, downregulated HTRA3 expression and inhibited the transcriptional activity of HTRA3, suggesting that HTRA3 was regulated negatively by FOXP1. In conclusion, our study demonstrates that HTRA3 is a repressor involved in OS development via the PTEN/PI3K/AKT pathway under the modulation of transcription factor FOXP1, and it may provide a therapeutic direction for OS patients.
尽管在理解骨肉瘤（OS）的生物学行为方面取得了最新进展，但OS仍然是危害儿童和青少年健康的最常见原发性骨肉瘤。高温需求A（HTRA）蛋白酶家族在众多恶性肿瘤中发挥重要调节作用，并作为一种预后生物标志物。然而，HTRA家族在OS发生发展中的功能和潜在机制仍不清楚。通过分析从不同基因表达综合数据库（GEO）获得的GSE126209数据集，我们发现作为HTRA家族成员的HTRA3在OS组织中与正常组织相比表达下调。功能实验表明，HTRA3过表达在体外抑制OS细胞的恶性行为，在体内抑制肿瘤生长。机制上，我们发现HTRA3与X连锁凋亡抑制蛋白（XIAP）共定位，并降低XIAP稳定性。进一步研究表明，XIAP敲低抑制了磷酸酶和张力蛋白同源物（PTEN）的降解，并且HTRA3导致PTEN/磷脂酰肌醇3-激酶（PI3K）/AKT通路受阻，其特征是在PTEN抑制剂BpV（HOpic）处理后HTRA3过表达引起的细胞功能逆转。详细研究表明，叉头框蛋白1（FOXP1）是OS进展中的一种癌基因，下调HTRA3表达并抑制HTRA3的转录活性，提示HTRA3受到FOXP1的负调控。总之，我们的研究表明，HTRA3是一种通过转录因子FOXP1调控下的PTEN/PI3K/AKT通路参与OS发生发展的抑制因子，它可能为OS患者提供治疗方向。
