Soft Substrate Promotes Osteosarcoma Cell Self-Renewal, Differentiation, and Drug Resistance Through miR-29b and Its Target Protein Spin 1
Soft Substrate Promotes Osteosarcoma Cell Self-Renewal, Differentiation, and Drug Resistance Through miR-29b and Its Target Protein Spin 1
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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、分化和耐药性
DOI：
10.1021/acsbiomaterials.0c00816
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发表时间：
2020-10-01
影响因子：
5.8
通讯作者：
Liu, Yiyao
中科院分区：
文献类型：
--
作者：
Li, Shun;Bai, Hongxia;Liu, Yiyao
细胞外基质（ECM）的硬化被认为是多步骤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刚度以维持癌症干细胞样能力方面发挥关键的调节作用。使用刚度为7、20和55 kPa的聚丙烯酰胺凝胶来模拟结缔组织、肌肉组织和骨组织的刚度。研究发现，骨肉瘤细胞的自我更新能力、分化潜能和耐药能力随着底物硬度的降低而增强，而扩散面积、增殖和迁移受到抑制。此外，miR-29在软底物培养的骨肉瘤细胞中明显下调，并且miR-29b-5p的异位表达显著抑制了与严重度相关的转录因子（Sox2、Nanog、Oct4）的表达和成球能力。软底物诱导的miR-29下调可以增加Spin 1的表达，激活磷脂酰肌醇3-激酶(PI3K)/Akt和Stat3信号通路，而这些信号通路被miR-29b-Sp的增加所抑制。综上所述，我们的研究结果阐明了miR-29可能是一种操纵骨肉瘤细胞严厉度的新型机械传感器。这一发现揭示了这样一个事实，即癌症生态位的机械提示可以通过操作microrna及其下游信号传导参与癌症进展的调节。
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 sternness 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 sternness-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-Sp. Taken together, our results elucidated that miR-29 could be a novel mechanical sensor which manipulates osteosarcoma cell sternness. 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.