膀胱癌新靶标miR-411的分子鉴定研究

Bladder cancer is a urinary system malignant tumor with high incidence. Although the overall 5 year survival of patients nearly 70%, the cost is very expensive. Early detection and prognosis are not only contribute to decreasing the economic pressure of patients, and also can provide theoretical guidance for the treatments to improve the therapeutic effect. However, the molecular targets can’t meet the needs of clinical diagnosis and treatment. Our recent study has demonstrated that miR-411 was down-regulated in both the primary animal model and clinical bladder cancer tissues. And the expression of miR-411 was positively correlated with the survival time of patients with bladder cancer. The over-expression of miR-411 can inhibit the proliferation of bladder cancer cells and increase the sensitivity of chemotherapy. So we demonstrate that the expression of miR-411 down-regulated is the significant incidence of the development process of bladder cancer. That is to say miR-411 may be a new target of bladder cancer diagnosis and prognosis. Thus we proposed on the basis of the preliminary work, to elaborate the function and mechanism of miR-411 in bladder cancer, and to make clearly that miR-411 is a new target in bladder cancer diagnosis. The exploration of the subject not only has important significance for bladder cancer early detection, prognosis and clinical medicine, but also contribute to promoting the research of against bladder cancer drug.

膀胱癌是泌尿系统高发恶性疾病，尽管患者总体5年生存期近70%，但其花费极其高昂，早期发现及预后诊断不仅有助于减轻患者经济压力，又可为治疗方案提供理论导向大大提高治疗效果，然而目前相关新分子靶标研究仍不能满足临床诊断及用药需求。我们最新的实验结果首次发现：膀胱癌原发动物模型与临床膀胱癌组织中miR-411表达均呈显著下调趋势，且miR-411表达与膀胱癌患者生存期有正相关性；过表达miR-411能显著抑制膀胱癌细胞增殖并增加化疗敏感性。我们据此推断miR-411的表达下调是导致膀胱癌发生发展过程中的重要分子事件，即miR-411可能成为膀胱癌诊断及防治研究中新的靶标。因此我们拟在前期工作基础上，系统阐述miR-411在膀胱癌中的功能及机制，并明确miR-411膀胱癌诊断新靶标。本课题的深入探索不仅对于膀胱癌早期发现、预后及临床用药有重要意义，也有助于推动抗膀胱癌新药研发等方面的应用基础研究。

本项目前期研究初步发现膀胱癌原发动物模型与临床膀胱癌组织中miR-411表达均呈显著下调趋势，且miR-411表达与膀胱癌患者生存期有正相关性；过表达miR-411能显著抑制膀胱癌细胞增殖并增加化疗敏感性。我们据此推断miR-411的表达下调是导致膀胱癌发生发展过程中的重要分子事件，即miR-411可能成为膀胱癌诊断及防治研究中新的靶标，但相关分子机制及生物学效应均不清楚。本项目旨在系统阐述miR-411在膀胱癌中的功能及机制，并明确miR-411膀胱癌诊断新靶标。通过项目资助研究，我们取得了可喜的成果，揭示了miR-411通过抑制其下游关键靶分子MLLT11发挥抑癌基因作用，即miR-411靶向mllt11 mRNA的3’UTR并下调其在人膀胱癌细胞中的蛋白表达；MLLT11作为miR-411下游调节基因介导其体外抑制膀胱癌的作用；我们还发现miR-411-MLLT11途径通过上调G2/M细胞周期抑制剂p21抑制膀胱癌细胞生长；miR-411在异种移植裸鼠模型中抑制体内肿瘤生长。据我们所知，这是首次证实miR-411/MLLT11/p21抑制细胞增殖的调控机制。这一新发现有利于我们进一步了解miR-411参与细胞增殖调控的分子机制。通过该项目的资助，基本完成了预期内容，累计发表标明资助SCI论文4篇，培养研究生2名，大幅提高了国内研究者实验室的研究水平，该项目成果不仅对于膀胱癌早期发现、预后及临床用药有重要意义 ，也有助于推动抗膀胱癌新药研发等方面的应用基础研究。