Department of Pathology, NYU Grossman School of Medicine New York, NY, United States of America.
Department of Orthopaedics and Sports Medicine, University of Florida, Gainesville, FL, United States of America.
PLoS One. 2023 Jan 26;18(1):e0278844. doi: 10.1371/journal.pone.0278844. eCollection 2023.
Leiomyosarcoma (LMS) is an aggressive, often poorly differentiated cancer of the smooth muscle (SM) lineage for which the molecular drivers of transformation and progression are poorly understood. In microRNA (miRNA) profiling studies, miR-130b was previously found to be upregulated in LMS vs. normal SM, and down-regulated during the differentiation of mesenchymal stem cells (MSCs) into SM, suggesting a role in LMS tumor progression. In the present study, the effects of miR-130b on human LMS tumorigenesis were investigated. Stable miR-130b overexpression enhanced invasion of LMS cells in vitro, and led to the formation of undifferentiated, pleomorphic tumors in vivo, with increased growth and metastatic potential compared to control LMS cells. TSC1 was identified as a direct miR-130b target in luciferase-3'UTR assays, and shRNA-mediated knockdown of TSC1 replicated miR-130b effects. Loss-of-function and gain-of-function studies showed that miR-130b levels regulate cell morphology and motility. Following miR-130b suppression, LMS cells adopted a rounded morphology, amoeboid mode of cell movement and enhanced invasive capacity that was Rho/ROCK dependent. Conversely, miR-130b-overexpressing LMS cells exhibited Rho-independent invasion, accompanied by down-regulation of Rho-pathway effectors. In mesenchymal stem cells, both miR-130b overexpression and TSC1 silencing independently impaired SM differentiation in vitro. Together, the data reveal miR-130b as a pro-oncogenic miRNA in LMS and support a miR-130b-TSC1 regulatory network that enhances tumor progression via inhibition of SM differentiation.
平滑肌肉瘤（LMS）是一种侵袭性的，通常分化不良的平滑肌（SM）谱系癌症，其转化和进展的分子驱动因素知之甚少。在 microRNA（miRNA）谱分析研究中，miR-130b 先前在 LMS 与正常 SM 中上调，并且在间充质干细胞（MSCs）分化为 SM 时下调，表明其在 LMS 肿瘤进展中发挥作用。在本研究中，研究了 miR-130b 对人 LMS 肿瘤发生的影响。稳定的 miR-130b 过表达增强了 LMS 细胞的体外侵袭能力，并导致体内未分化的多形性肿瘤的形成，与对照 LMS 细胞相比，生长和转移潜力增加。TSC1 被鉴定为荧光素酶-3'UTR 测定中的直接 miR-130b 靶标，并且 shRNA 介导的 TSC1 敲低复制了 miR-130b 的作用。功能丧失和功能获得研究表明，miR-130b 水平调节细胞形态和运动。在 miR-130b 抑制后，LMS 细胞采用圆形形态，阿米巴样细胞运动方式，并增强 Rho/ROCK 依赖性侵袭能力。相反，过表达 miR-130b 的 LMS 细胞表现出 Rho 非依赖性侵袭，同时下调 Rho 通路效应物。在间充质干细胞中，miR-130b 过表达和 TSC1 沉默都独立地损害了体外 SM 分化。总之，数据显示 miR-130b 是 LMS 中的致癌 miRNA，并支持 miR-130b-TSC1 调节网络，通过抑制 SM 分化来增强肿瘤进展。
