组蛋白乙酰化修饰调控miR-1181-SOX2轴在口腔白斑病发生发展中的作用及机制研究

Abnormal modification of histone acetylation is one of the pathogenic mechanisms of many major diseases. In our preliminary studies, we observed that the increased abundance of pluripotency-related gene SOX2 was significantly correlated to the initiation and progression of oral leukoplakia(OLK), while the level of histone acetylation decreased in dysplastic oral keratinocyte (DOK) cells. Treatment with selective class I histone deacetylase inhibitor (HDACi) significantly enhanced the acetylation status of DOK, and suppressed expression of SOX2 . All above results indicate that modification of histone acetylation is involved in the regulation of epithelial cell stemness in the progression of OLK. Our further studies found that alterations of histone acetylation in miR-1181 promoter region could influence the expression of SOX2, which was the target gene of miR-1181. Then, we hypothesize that histone acetylation-miR-1181-SOX2 axis might play important roles during the development of OLK by modulating the gain of stem cell-like properties of epithelial cells. Furthermore, therapies targeting histone acetylation may suppress or reverse the initiation and progression of OLK. Therefore, by means of animal model, clinical study and so on, we set out to investigate potential molecular mechanisms underlying the function of histone acetylation-miR-1181-SOX2 axis in the regulation of epithelial cell stemness, and its role in the development of OLK. Furthermore, we try to examine the perspective and significance of selective HDACi in the treatment of OLK. All those results would be helpful to provide novel insight into the role of histone acetylation in the development of OLK, and then provide new therapeutic targets for OLK.

组蛋白乙酰化异常是多种重大疾病的发生机制之一。我们前期已发现，细胞干性因子SOX2在口腔白斑病发生发展中表达依次上调，而异常增生口腔上皮细胞组蛋白乙酰化降低；采用选择性I类组蛋白去乙酰化酶抑制剂（HDACi）作用后细胞组蛋白乙酰化增加、SOX2表达降低，提示组蛋白乙酰化修饰可调控白斑演变中上皮细胞干性。进一步研究发现，miR-1181启动子区组蛋白乙酰化水平改变可影响其靶基因SOX2的表达。因此，我们提出以下假设：组蛋白乙酰化修饰-miR-1181-SOX2轴可调控上皮细胞干性，从而参与口腔白斑病的发生发展；靶向干预组蛋白乙酰化可阻逆白斑病的演变。为此，本项目拟通过临床研究、模式动物等多层面探讨组蛋白乙酰化通过miR-1181-SOX2轴调控上皮细胞干性的机制及其在白斑病中的作用，分析选择性HDACi的干预前景与意义。旨在为阐明组蛋白乙酰化在白斑病演变中的作用提供新的重要证据和防治新靶点。

组蛋白乙酰化异常是多种重大疾病的发生机制之一。口腔白斑病属于口腔潜在恶性疾患（OPMD），我们深入探讨了其演变机制与干预策略。①组蛋白乙酰化修饰可调控SOX2相关的细胞干性且与口腔白斑病的发生发展密切相关；一种新型I类组蛋白去乙酰化酶抑制剂4SC-202与INK128（mTORC1/C2抑制剂）联合治疗可显著抑制大鼠口腔黏膜癌变与肿瘤复发；两者联用通过miR-429/miR-1181介导的mRNA降解和阻止带帽依赖的mRNA翻译来抑制SOX2表达，两者在抑制细胞增殖和干性方面具有协同作用。此外，4SC-202与常见降糖药二甲双胍联用可通过调控STAT3/Twist1抑制OSCC的侵袭和迁移，为老药新用、缩短药物研发周期、探讨更优的口腔白斑治疗新方案提供了思路。②此外，我们研究发现了OSCC潜在新的诊断及预后相关生物标志物及预后预测模型，如唾液外泌体miR-24-3p、免疫相关lncRNA等。③探讨了OPMD演变新机制，发现了治疗新靶点。高脂饮食诱导肥胖可增加OPMD癌变风险，其通过募集和增强MDSCs的功能加速口腔癌变；他克莫司通过调控细胞周期抑制口腔癌变发生；KRAS G12D突变通过上调Runx1促进OSCC发生发展；LncRNA-BANCR可促进OSCC侵袭和转移；转录因子SPDEF通过转录激活NR4A1抑制HNSCC发生发展；靶向PRMT5可通过抑制Twist1转录来延缓HNSCC的癌变和转移；应激诱导蛋白SESN1和过氧化物蛋白可调控HNSCC增殖、侵袭和转移；miR-411-5p通过靶向RYBP促进的淋巴结转移。④探究了OPMD及OSCC治疗并发症及组织修复不良的机理，建立了口腔软硬组织缺损修复新策略。研究发现放疗通过Ca2+/CaN/NFATc1/Fis介导的线粒体分裂抑制BMSCs成骨分化导致骨破坏；甲磺酸去铁胺可激活内皮-周细胞间PDGF-BB/PDGFRβ信号改善PDGFRβ周细胞功能，最终从成血管和成骨两个方向协同减轻放疗骨损伤；一种包裹雪旺细胞来源外泌体的组织工程水凝胶可促进神经支配、免疫调节、血管化和成骨而协调骨愈合微环境；研发了一种形状可编程的层级结构复合膜体系，通过协同调节炎症微环境有效促进糖尿病创面的修复与再生，为临床口腔组织创面修复治疗提供了新策略。