Soft Substrate Promotes Osteosarcoma Cell Self-Renewal, Differentiation, and Drug Resistance Through miR-29b and Its Target Protein Spin 1,ACS Biomaterials Science & Engineering

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Soft Substrate Promotes Osteosarcoma Cell Self-Renewal, Differentiation, and Drug Resistance Through miR-29b and Its Target Protein Spin 1
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2020-09-16 , DOI: 10.1021/acsbiomaterials.0c00816
Shun Li ₁ , Hongxia Bai ₁ , Xiangyan Chen ₁ , Shengnan Gong ₁ , Jinman Xiao ₁ , Dan Li ₁ , Li Li ₁ , Ying Jiang ₁ , Tingting Li ₁ , Xiang Qin ₁ , Hong Yang ₁ , Chunhui Wu ₁ , Fengming You ₂ , Yiyao Liu _{1,

2}

Affiliation

Stiffening of the extracellular matrix (ECM) is considered a typical remolding of the microenvironment in multistep tumor progression. However, the molecular mechanisms by which the tumor cell responds to the ECM mechanical cues remain elusive. Here, we demonstrated that microRNA-29b (miR-29b) and its downstream signaling play critical regulatory roles that osteosarcoma cells sense the ECM stiffness to maintain the cancer stem cell-like ability. Polyacrylamide gels with a stiffness of 7, 20, and 55 kPa were used to mimic the rigidity of connective tissue, muscle tissue, and bone tissue. It was found that the stemness properties including self-renewal ability, differentiation potential, and drug resistance of osteosarcoma cells were strongly enhanced with reducing substrate stiffness, whereas spreading area, proliferation, and migration were inhibited. Moreover, miR-29 was obviously downregulated in soft substrate-cultured osteosarcoma cells, and the expression of stemness-related transcription factors (Sox2, Nanog, and Oct4) and the sphere formation ability were significantly inhibited by ectopic expression of miR-29b-5p. The soft substrate-induced miR-29 downregulation could increase Spin 1 expression and activate phosphatidylinositol 3-kinase (PI3K)/Akt and Stat3 signaling, which were suppressed by the increase in miR-29b-5p. Taken together, our results elucidated that miR-29 could be a novel mechanical sensor which manipulates osteosarcoma cell stemness. This finding uncovers the fact that the mechanical cue of the cancer niche could take part in the regulation of cancer progression through operating microRNAs and their downstream signaling.

中文翻译：

软基质通过 miR-29b 及其靶蛋白 Spin 1 促进骨肉瘤细胞自我更新、分化和耐药

细胞外基质 (ECM) 的硬化被认为是多步肿瘤进展中微环境的典型重塑。然而，肿瘤细胞对 ECM 机械信号作出反应的分子机制仍然难以捉摸。在这里，我们证明了 microRNA-29b (miR-29b) 及其下游信号传导在骨肉瘤细胞感知 ECM 硬度以维持癌症干细胞样能力方面发挥着关键的调节作用。硬度为 7、20 和 55 kPa 的聚丙烯酰胺凝胶用于模拟结缔组织、肌肉组织和骨组织的硬度。研究发现，随着基质硬度的降低，骨肉瘤细胞的自我更新能力、分化潜能和耐药性等干性特性显着增强，而扩散面积、增殖、和迁移受到抑制。此外，miR-29在软基质培养的骨肉瘤细胞中明显下调，miR-29b-5p的异位表达显着抑制干性相关转录因子（Sox2、Nanog和Oct4）的表达和球体形成能力。 . 软底物诱导的 miR-29 下调可增加 Spin 1 的表达并激活磷脂酰肌醇 3-激酶 (PI3K)/Akt 和 Stat3 信号传导，这些信号传导被 miR-29b-5p 的增加所抑制。总之，我们的结果阐明了 miR-29 可能是一种操纵骨肉瘤细胞干性的新型机械传感器。这一发现揭示了这样一个事实，即癌症生态位的机械线索可以通过操作 microRNA 及其下游信号传导参与癌症进展的调节。miR-29在软基质培养的骨肉瘤细胞中明显下调，miR-29b-5p的异位表达显着抑制干性相关转录因子（Sox2、Nanog和Oct4）的表达和球体形成能力。软底物诱导的 miR-29 下调可增加 Spin 1 的表达并激活磷脂酰肌醇 3-激酶 (PI3K)/Akt 和 Stat3 信号传导，这些信号传导被 miR-29b-5p 的增加所抑制。总之，我们的结果阐明了 miR-29 可能是一种操纵骨肉瘤细胞干性的新型机械传感器。这一发现揭示了这样一个事实，即癌症生态位的机械线索可以通过操作 microRNA 及其下游信号传导参与癌症进展的调节。miR-29在软基质培养的骨肉瘤细胞中明显下调，miR-29b-5p的异位表达显着抑制干性相关转录因子（Sox2、Nanog和Oct4）的表达和球体形成能力。软底物诱导的 miR-29 下调可增加 Spin 1 的表达并激活磷脂酰肌醇 3-激酶 (PI3K)/Akt 和 Stat3 信号传导，这些信号传导被 miR-29b-5p 的增加所抑制。总之，我们的结果阐明了 miR-29 可能是一种操纵骨肉瘤细胞干性的新型机械传感器。这一发现揭示了这样一个事实，即癌症生态位的机械线索可以通过操作 microRNA 及其下游信号传导参与癌症进展的调节。

更新日期：2020-10-12

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