TM4SF1 involves in miR-1-3p/miR-214-5p-mediated inhibition of the migration and proliferation in keloid by regulating AKT/ERK signaling
TM4SF1 involves in miR-1-3p/miR-214-5p-mediated inhibition of the migration and proliferation in keloid by regulating AKT/ERK signaling
复制标题
TM4SF1 通过调节 AKT/ERK 信号参与 miR-1-3p/miR-214-5p 介导的瘢痕疙瘩迁移和增殖抑制
DOI：
10.1016/j.lfs.2020.117746
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发表时间：
2020
期刊：
影响因子：
6.1
通讯作者：
Jinghong Xu
中科院分区：
文献类型：
--
作者：
Mingyuan Xu;Jiaqi Sun;Yijia Yu;Qianqian Pang;Xiaohu Lin;May Barakat;Rui Lei;Jinghong Xu
目的：跨膜4 L六家族成员1（TM 4SF 1）是一种在癌症中高度表达的小质膜糖蛋白。然而，TM 4SF 1在瘢痕疙瘩中的作用仍然未知。本研究旨在探讨TM 4SF 1在瘢痕疙瘩中的表达、功能及其microRNA（microRNA，miRNA）调控网络。应用双荧光素酶报告基因测定来确定miRNA靶标。免疫组化、Western blotting、qRT-PCR、创伤愈合试验、Transwell试验、细胞计数kit-8试验和流式细胞术也在本研究中使用。TM 4SF 1的下调可显著抑制HKFs的增殖和迁移，并诱导HKFs凋亡。此外，si-TM 4SF 1抑制AKT/ERK信号通路。同时，上调TM 4SF 1表达可促进人包皮成纤维细胞（HFF-1）的增殖、迁移和AKT/ERK信号通路的激活。此外，TM 4SF 1还受到miRNAs的调控，miRNAs通过转录后调节基因表达在瘢痕疙瘩中发挥重要作用。经筛选，发现miR-1- 3 p和miR-214- 5 p靶向TM 4SF 1，抑制TM 4SF 1的表达，抑制细胞增殖、迁移，并诱导细胞凋亡。结论miR-1 - 3 p、miR-214 - 5 p和TM 4SF 1在瘢痕疙瘩中的表达与细胞增殖、运动和凋亡有关，提示它们可能是瘢痕疙瘩治疗的潜在靶点。
AimsTransmembrane 4 L six family member 1 (TM4SF1) is a small plasma membrane glycoprotein that is highly expressed in cancers. However, the role of TM4SF1 that plays in keloids remains unknown. We investigated the expression, function and the microRNA (miRNA) regulatory network of TM4SF1 in keloids.Main methodsSmall interfering RNAs and lentivirus were used to alter the expression of TM4SF1 in fibroblasts. Dual-luciferase reporter assays were applied to determine the miRNA targets. Immunohistochemistry, western blotting, qRT-PCR, wound healing assays, Transwell assays, cell count kit-8 assays and flow cytometry were also employed in this study.Key findingsTM4SF1 was frequently upregulated in human keloid fibroblasts (HKFs) compared with human normal skin fibroblasts (HSFs). The downregulation of TM4SF1 significantly inhibited proliferation and migration, and induced apoptosis in HKFs. Furthermore, si-TM4SF1 inhibited the AKT/ERK signaling. Meanwhile, the upregulation of TM4SF1 promoted proliferation, migration and the activation of AKT/ERK signaling in human foreskin fibroblasts (HFF-1). Moreover, TM4SF1 can be regulated by miRNAs, which have been validated to play important roles in keloids by posttranscriptional regulation of gene expression. After screening, we found miR-1-3p and miR-214-5p targeted TM4SF1, inhibited TM4SF1 expression, cell proliferation, migration, and induced apoptosis in HKFs. And the level of miR-1-3p and miR-214-5p were found lower in HKFs than in HSFs.SignificanceOur study demonstrates a novel regulatory mechanism by which miR-1-3p, miR-214-5p, and TM4SF1 are involved in proliferation, cell motility, and apoptosis, suggesting that they may be potential targets in therapies for keloids.