Department of Oral and Maxillofacial Surgery, Xiangya Stomatological Hospital of Central South University, Central South University, Changsha, China.
Xiangya School of Stomatology, Central South University, Changsha, China.
J Oral Pathol Med. 2024 Aug;53(7):468-479. doi: 10.1111/jop.13559. Epub 2024 May 27.
circRNAs have been shown to participate in diverse diseases; however, their role in oral submucous fibrosis (OSF), a potentially malignant disorder, remains obscure. Our preliminary experiments detected the expression of circRNA mitochondrial translation optimization 1 homologue (circMTO1) in OSF tissues (n = 20) and normal mucosa tissues (n = 20) collected from Hunan Xiangya Stomatological Hospital, and a significant decrease of circMTO1 expression was showed in OSF tissues. Therefore, we further explored circMTO1 expression in OSF.
Target molecule expression was detected using RT-qPCR and western blotting. The migration and invasion of buccal mucosal fibroblasts (BMFs) were assessed using wound healing and Transwell assays. The interaction between miR-30c-5p, circMTO1, and SOCS3 was evaluated using dual luciferase, RNA immunoprecipitation (RIP), and RNA pull-down assays. The colocalisation of circMTO1 and miR-30c-5p was observed using fluorescence in situ hybridisation (FISH).
circMTO1 and SOCS3 expression decreased, whereas miR-30c-5p expression increased in patients with OSF and arecoline-stimulated BMFs. Overexpression of circMTO1 effectively restrained the fibroblast-myofibroblast transition (FMT), as evidenced by the increase in expression of Coll I, α-SMA, Vimentin, and the weakened migration and invasion functions in BMFs. Mechanistic studies have shown that circMTO1 suppresses FMT by enhancing SOCS3 expression by sponging miR-30c-5p and subsequently inactivating the FAK/PI3K/AKT pathway. FMT induced by SOCS3 silencing was reversed by the FAK inhibitor TAE226 or the PI3K inhibitor LY294002.
circMTO1/miR-30c-5p/SOCS3 axis regulates FMT in arecoline-treated BMFs via the FAK/PI3K/AKT pathway. Expanding the sample size and in vivo validation could further elucidate their potential as therapeutic targets for OSF.
circRNAs 已被证明参与多种疾病；然而，它们在口腔黏膜下纤维性变（OSF）中的作用，一种潜在的恶性疾病，仍然不清楚。我们的初步实验检测到 circRNA 线粒体翻译优化 1 同源物（circMTO1）在 OSF 组织（n=20）和湖南湘雅口腔医院正常黏膜组织（n=20）中的表达，OSF 组织中 circMTO1 的表达明显降低。因此，我们进一步研究了 circMTO1 在 OSF 中的表达。
使用 RT-qPCR 和 Western blot 检测靶分子表达。使用划痕愈合和 Transwell 测定评估颊黏膜成纤维细胞（BMFs）的迁移和侵袭。使用双荧光素酶、RNA 免疫沉淀（RIP）和 RNA 下拉测定评估 miR-30c-5p、circMTO1 和 SOCS3 之间的相互作用。使用荧光原位杂交（FISH）观察 circMTO1 和 miR-30c-5p 的共定位。
OSF 患者和槟榔碱刺激的 BMFs 中 circMTO1 和 SOCS3 表达降低，miR-30c-5p 表达升高。circMTO1 的过表达有效抑制了成纤维细胞-肌成纤维细胞转化（FMT），表现为 Coll I、α-SMA、Vimentin 的表达增加，以及 BMFs 迁移和侵袭功能的减弱。机制研究表明，circMTO1 通过海绵吸附 miR-30c-5p 增强 SOCS3 表达，从而抑制 FAK/PI3K/AKT 通路，抑制 FMT。SOCS3 沉默诱导的 FMT 被 FAK 抑制剂 TAE226 或 PI3K 抑制剂 LY294002 逆转。
circMTO1/miR-30c-5p/SOCS3 轴通过 FAK/PI3K/AKT 通路调节槟榔碱处理的 BMFs 中的 FMT。扩大样本量和体内验证可以进一步阐明它们作为 OSF 治疗靶点的潜力。
