组蛋白修饰调控miRNAs在胰腺癌干细胞干性维持中的作用

Cancer stem cell is an initiating factor in pancreatic cancer initiation, progression, metastasis, recurrence, and drug resistance and the maintenance of its stemness is crucial. Pancreatic cancer can be cured by destroying the cancer stem cell, but the molecular mechanisms of stemness maintenance of pancreatic cancer stem cell need to be demonstrated. CXCR4 is the key molecule to maintain the stemness of pancreatic cancer stem cells. Our preliminary research has confirmed that miR-139 and miR-146a can target CXCR4 3`-UTR to inhibit its expression and the acetylating modification state of histone is involved in the regulation of these miRNAs. Based on this, through cytological experiments and tumor-bearing nude mice model, CD133+CXCR4+ pancreatic cancer stem cells will be established to detect the expression of miR-139 and miR-146a, and the histone modification status of these miRNAs gene promoter region. By overexpression of miR-139 and miR-146a in pancreatic cancer stem cell and observing whether miRNAs affects the maintenance of its stemness which includes self-renewal, proliferation, invasion and metastasis, gemcitabine-resistant and high-tumorigenic. It is designed to reveal the role of miRNAs in the maintenance of stemness of pancreatic cancer stem cell, the histone modification mechanism of regulation of miRNAs expression, as well as the new molecular mechanism for stemness maintenance, which can provide a new strategy for pancreatic cancer treatment, and is of important theoretical significance and practical value.

肿瘤干细胞是胰腺癌发生、发展、转移、复发、耐药的始动因素，其干性维持很关键，通过消灭肿瘤干细胞可以治疗胰腺癌，但需要明确胰腺癌干细胞干性维持的分子机制。CXCR4是胰腺癌干细胞干性维持的重要分子，我们前期工作证实miR-139、miR-146a能抑制CXCR4的表达，发现组蛋白乙酰化修饰能调控miRNAs基因表达。在此基础上，我们筛选获得CD133+CXCR4+胰腺癌干细胞，检测细胞中miR-139、miR-146a表达水平及miRNA基因启动子区组蛋白修饰状态；通过在胰腺癌干细胞中过表达miR-139、miR-146a，观察miRNAs是否影响胰腺癌干细胞干性维持：自我更新、生长增殖、侵袭转移、吉西他滨耐药、高致瘤性；旨在揭示胰腺癌干细胞干性维持中miRNAs的作用及其表达调控的组蛋白修饰机制，试图阐明胰腺癌干细胞干性维持的新机制，为治疗胰腺癌提供新策略，具有重要理论意义和实际应用价值。