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Knockdown of STAT3 targets a subpopulation of invasive melanoma stem‐like cells

机译:Stat3的敲低针对侵入性黑色素瘤干细胞的亚群

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Abstract Transcription factor signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many cancers, including melanomas. Active, phosphorylated STAT3 contributes to tumor growth and formation of the immunosuppressive tumor microenvironment. Recent evidence suggests an important role of STAT3 in self‐renewal of cancer stem‐like cells (CSCs). In the present study, we aimed to determine the expression and role of active STAT3 in melanoma CSCs. We found the increased levels of phosphorylated (Y705) STAT3 in CSC sphere cultures derived from three human and murine melanoma cells. Knockdown of STAT3 did not affect basal proliferation, but reduced sphere forming capacity of two human melanoma cell lines. Moreover, the level of active STAT3 was elevated in rhodamine 123 negative subpopulations of CSCs sorted from three melanoma cell lines. We found that focal adhesion kinase (FAK) and AKT signaling pathways, implicated in the regulation of cell migration and invasion, were up‐regulated in melanoma CSCs. Moreover, expression of SERPINA3 , which regulates melanoma invasion, was increased in melanoma CSCs sphere cultures, which correlated with augmented cell invasion in Matrigel. Our findings show that STAT3 is activated and supports maintenance of melanoma CSCs. It suggests that STAT3 could serve as a potential target to impair tumor progression or recurrence.
机译:摘要转录因子信号传感器和转录3(STAT3)的活化剂在许多癌症中组成型激活,包括黑色素瘤。活性磷酸化的Stat3有助于肿瘤生长和免疫抑制肿瘤微环境的形成。最近的证据表明STAT3在癌症干细胞(CSC)的自我更新中的重要作用。在本研究中,我们旨在确定活性STAT3在黑素瘤CSCs中的表达和作用。我们发现来自三种人和小鼠黑素瘤细胞的CSC球体培养物中的磷酸化(Y705)STAT3的水平增加。 Stat3的敲低不影响基础增殖,而是降低了两种人黑素瘤细胞系的球形形成能力。此外,在从三黑色素瘤细胞系中排序的CSC的Rodamine 123阴性群中升高了活性STAT3的水平。我们发现局灶性粘附激酶(FAK)和AKT信号传导途径,其涉及细胞迁移和侵袭,在黑素瘤CSC中调节。此外,调节黑素瘤侵袭的Serpina3的表达在黑素瘤CSCS球形培养中增加,与Matrigel中的增强细胞侵袭相关。我们的研究结果表明Stat3被激活并支持Melanoma CSC的维护。它表明Stat3可以作为患有患有肿瘤进展或复发的潜在目标。

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