CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
缺氧预处理间充质干细胞来源 HIF-1α 刺激的 PGRN/MAPK 轴激活促进骨肉瘤进展
英文原题：Activation of PGRN/MAPK axis stimulated by the hypoxia-conditioned mesenchymal stem cell-derived HIF-1α facilitates osteosarcoma progression.
查看英文原题
Activation of PGRN/MAPK axis stimulated by the hypoxia-conditioned mesenchymal stem cell-derived HIF-1α facilitates osteosarcoma progression.
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研究概要
我们得出结论，由缺氧 MSC 来源的 HIF-1 升高所激活的 PGRN，通过激活 MAPK 信号通路促进骨肉瘤进展。
中文摘要
颗粒蛋白前体（PGRN）是多种癌症进展的重要存活因子。
探究PGRN对骨肉瘤（OS）细胞恶性生物学行为的影响和机制，以及间充质干细胞（MSC）和缺氧微环境对PGRN变化的影响。
评估OS组织和细胞系中PGRN的表达模式。随后通过功能缺失实验研究PGRN对OS细胞增殖、迁移和细胞死亡的作用。采用蛋白质印迹和功能实验并辅以skatole，检测该过程中的MAPK信号激活。此外，在MSC中敲低缺氧诱导因子1（HIF-1），并外源性添加HIF-1（exo-HIF-1），以探究MSC如何影响PGRN变化及OS细胞恶性行为。
OS中PGRN异常高表达，并与患者预后不良相关。敲低PGRN可抑制OS细胞增殖和迁移并诱导细胞死亡；激活MAPK通路可逆转这些作用。进一步证据显示，MSC可调节PGRN，进而介导OS细胞恶性生物学行为。缺氧增强MSC中HIF-1表达。缺氧条件下敲低MSC中的HIF-1可抑制MSC的致癌作用并降低OS细胞PGRN表达，而外源性HIF-1处理则产生相反作用。
研究表明缺氧环境中的MSC可通过HIF-1调控PGRN，促进OS细胞恶性行为；PGRN/MAPK通路可能成为潜在治疗靶点。
展开英文摘要原文
Progranulin (PGRN) is an important survival factor in the progression of multiple cancers.
To explore the effects and mechanisms of PGRN on malignant biological behavior of osteosarcoma (OS) cells and the effects of mesenchymal stem cells (MSCs) and the hypoxic microenvironment on PGRN alteration. MATERIAL AND METHODS: The expression pattern of PGRN in OS were evaluated in OS tissues and cell lines. Next, a loss-of-function assay investigated the function of PGRN on the proliferation, migration and cell death of OS cells. The activation of MAPK signaling in the process was examined by western blot and functional experiments accompanied by skatole. Additionally, we internally silenced hypoxia-inducible factor-1 (HIF-1 ) in MSCs along with exogenously added HIF-1 (exo-HIF-1 ) to explore how MSCs affect PGRN alteration and the malignant behavior of OS cells.
An aberrantly high expression of PGRN was observed in OS and associated with the poor prognosis of OS patients. PGRN knockdown repressed the proliferation, migration and induced cell death of OS cells, and activating MAPK pathway reversed these effects. Further evidence showed that MSCs regulated PGRN to mediate the malignant biological behavior of OS cells. Hypoxia enhanced HIF-1 expression in MSCs. HIF-1 silencing in MSCs under hypoxia suppressed the oncogenic effects of MSCs and reduced PGRN expression in OS cells, while the treatment of exo-HIF-1 reversed the depressive effects of HIF1 silencing on OS progression.
Overall, we concluded that PGRN, which was activated by the increase of hypoxic-MSCs-derived HIF-1 , promoted OS progression through the activation of MAPK signaling.
论文信息
- 作者
- Shang C、Ou X、Zhang H、Wei D、Wang Q、Li G
- 第一作者单位
- Department of the Second Hand Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710054, China.China
- 通讯作者单位
- Department of the First Hand Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710054, China. Electronic address: ligang838@126.com.China
- 期刊
- Experimental cell research2022 Dec 1
- 原文标识
- PubMed 36183781 · DOI 10.1016/j.yexcr.2022.113373