miR-374b/NF-kB正反馈环路促进膀胱尿路上皮癌发生发展的机制研究

NF-kB involved in the pathopoiesis of cancer. Bladder cancer is the most common malignant tumor of the urinary system . The crucial roles of miRNA in carcinogenesis have been well emphasized. In our investigation, the differential expression of miRNA in bladder urothelial carcinoma and adjacent normal bladder tissue has been investigated using miRNA microarray and real-time quantitative PCR technology. We found that miR-374b was specificly induced in the bladder urothelial carcinoma tissue and could inhibit the growth of tumor in nude mice. The further result indicate that miR-374b may be as carcinogenic miRNA through direct inhibiting IFRD1 expression level to activate the NF-kB signaling pathway, thereby promoting the development of bladder epithelial carcinoma. The more interesting thing is that further result demonstrated that transcription of miR-374b might be regulated by NF-kB pathway. Thus, it suggested that the positive feedback loop of miR-374b/NF-kB promotes the development of bladder urothelial carcinoma. The clarification of this positive feedback loop will explain the functional mechanism of miRNA abnormal expression in cancer cells and could promote the investigation the pathogenic mechanism of bladder urothelial carcinoma .

转录因子NF-kB异常活化与多种肿瘤发生发展相关。膀胱癌是泌尿系统最常见的恶性肿瘤。microRNA异常表达与肿瘤演进关系密切。我们在实验中获得了膀胱尿路上皮癌特异性miRNA表达谱，并发现miR-374b在膀胱癌组织表达水平明显升高，裸鼠荷瘤实验结果表明阻断miR-374b能够明显抑制肿瘤生长。进一步的研究结果表明miR-374b作为一种致癌miRNA通过直接抑制IFRD1表达水平激活了NF-kB信号通路，从而促进了膀胱尿路上皮癌发生发展。更为有意思的是，我们的实验结果表明miR-374b的转录受NF-kB调节。以上结果提示miR-374b与NF-kB之间可能通过形成正反馈回路，促进了膀胱尿路上皮癌的发生发展。本课题中我们将在前期实验的基础上，对此正反馈回路的机制进行详细解析，为miRNA在癌细胞中异常表达的原因及作用的揭示提供更多的依据，进一步推动膀胱癌发生发展机制的研究。

膀胱癌是泌尿系统最常见的肿瘤，深入探讨研究膀胱癌病因学相关机制，具有重要的临床意义。我们发现miR-374b在膀胱癌组织表达水平明显升高，裸鼠荷瘤实验结果表明阻断miR-374b能够明显抑制肿瘤生长；进一步的研究结果表明miR-374b作为一种致癌miRNA通过直接抑制IFRD1表达水平激活了NF-kB信号通路，从而促进了膀胱尿路上皮癌发生发展。另外，我们发现FGF13基因在膀胱癌细胞内显著低表达，免疫组化分析证实，FGF13蛋白在肿瘤组织中的表达低于瘤旁正常组织；更进一步发现过表达FGF13可以促进膀胱癌细胞凋亡，抑制其增殖能力和迁移能力；更重要的是我们发现FGF13的表达水平与患者肿瘤侵袭程度呈反向相关。 另外，我们发现正义链长链非编码RNA (LncRNA) NONHSAT070806在大部分患者膀胱癌组织中表达水平下降，且其表达水平与患者肿瘤侵袭程度呈负相关；NONHSAT070806过表达可诱导细胞凋亡，抑制细胞增殖、迁移、侵袭和细胞克隆形成能力以及体内抑制膀胱癌细胞成瘤能力。本研究发现的与膀胱癌发生发展密切相关的miRNA、蛋白和LncRNA，不仅推进了膀胱癌致病机制的基础研究，而且为其在预防和治疗提供了新的潜在靶点。