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miR-214-3p通常被EWS-FLI1和CD99下调，其恢复可限制尤因肉瘤的侵袭性。

miR-214-3p Is Commonly Downregulated by EWS-FLI1 and by CD99 and Its Restoration Limits Ewing Sarcoma Aggressiveness.

作者信息

De Feo Alessandra, Pazzaglia Laura, Ciuffarin Lisa, Mangiagli Fabio, Pasello Michela, Simonetti Elisa, Pellegrini Evelin, Ferrari Cristina, Bianchi Giuseppe, Spazzoli Benedetta, Scotlandi Katia

机构信息

SSD Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy.

IRCCS Istituto Ortopedico Rizzoli, Third Orthopaedic Clinic and Traumatology, 40136 Bologna, Italy.

出版信息

Cancers (Basel). 2022 Mar 30;14(7):1762. doi: 10.3390/cancers14071762.

DOI:10.3390/cancers14071762
PMID:35406534
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8997046/
Abstract

Ewing's sarcoma (EWS), an aggressive pediatric bone and soft-tissue sarcoma, has a very stable genome with very few genetic alterations. Unlike in most cancers, the progression of EWS appears to depend on epigenetic alterations. EWS-FLI1 and CD99, the two hallmarks of EWS, are reported to severely impact the malignancy of EWS cells, at least partly by regulating the expression of several types of non-coding RNAs. Here, we identify miR-214-3p as a common mediator of either EWS-FLI1 or CD99 by in silico analysis. MiR-214-3p expression was lower in EWS cells and in clinical samples than in bone marrow mesenchymal stem cells, and this miRNA was barely expressed in metastatic lesions. Silencing of EWS-FLI1 or CD99 restored the expression of miR-214-3p, leading to a reduced cell growth and migration. Mechanistically, miR-214-3p restoration inhibits the expression of the high-mobility group AT-hook 1 (HMGA1) protein, a validated target of miR-214-3p and a major regulator of the transcriptional machinery. The decrease in HMGA1 expression reduced the growth and the migration of EWS cells. Taken together, our results support that the miR-214-3p is constitutively repressed by both EWS-FLI1 and CD99 because it acts as an oncosuppressor limiting the dissemination of EWS cells.

摘要

尤因肉瘤（EWS）是一种侵袭性儿童骨与软组织肉瘤，其基因组非常稳定，几乎没有基因改变。与大多数癌症不同，EWS的进展似乎依赖于表观遗传改变。EWS的两个标志性特征EWS-FLI1和CD99据报道至少部分通过调节几种非编码RNA的表达来严重影响EWS细胞的恶性程度。在此，我们通过计算机分析确定miR-214-3p是EWS-FLI1或CD99的共同介导因子。EWS细胞和临床样本中miR-214-3p的表达低于骨髓间充质干细胞，并且这种微小RNA在转移病灶中几乎不表达。沉默EWS-FLI1或CD99可恢复miR-214-3p的表达，导致细胞生长和迁移减少。从机制上讲，miR-214-3p的恢复抑制了高迁移率族AT钩蛋白1（HMGA1）的表达，HMGA1是miR-214-3p的一个已验证靶点，也是转录机制的主要调节因子。HMGA1表达的降低减少了EWS细胞的生长和迁移。综上所述，我们的结果支持miR-214-3p被EWS-FLI1和CD99组成性抑制，因为它作为一种肿瘤抑制因子限制了EWS细胞的扩散。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48c3/8997046/193776469373/cancers-14-01762-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48c3/8997046/cddbdc0a7f84/cancers-14-01762-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48c3/8997046/f1041bcb08e1/cancers-14-01762-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48c3/8997046/0c389d72e2e8/cancers-14-01762-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48c3/8997046/022b90683978/cancers-14-01762-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48c3/8997046/fd6a093e8dc5/cancers-14-01762-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48c3/8997046/193776469373/cancers-14-01762-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48c3/8997046/cddbdc0a7f84/cancers-14-01762-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48c3/8997046/f1041bcb08e1/cancers-14-01762-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48c3/8997046/0c389d72e2e8/cancers-14-01762-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48c3/8997046/022b90683978/cancers-14-01762-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48c3/8997046/fd6a093e8dc5/cancers-14-01762-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48c3/8997046/193776469373/cancers-14-01762-g006.jpg

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