MIIP对miR-8072的转录调控及其在乳腺癌发生发展中的作用研究

In our previous studies, we discovered that migration and invasion inhibitory protein(MIIP) could inhibit the proliferation, migration and invasion of breast cancer cells, overexpression of MIIP upregulated the expression of miR-8072. Futhermore, miR-8072 exhibited effect of preventing tumorigenesis of breast cancer. Along with the results that MIIP is located in cytoplasm and nucleus, and cytoplasmic localization of MIIP is associated with occurrence of breast cancer, we speculate that subcellular location of MIIP may influence its anti-tumor function, and MIIP may act as a transcription factor or transcriptional coregulator to regulate the expression of oncogene or tumor suppressor, including miRNAs. In this project, we will reveal the function and possible mechanism of MIIP in regulating the expression of miR-8072, explore the elements determining the subcellular localization of MIIP, and illustrate the role of miR-8072 in tumorigenesis and progression, through a series of research approaches. This project will broaden our knowledge on the function of MIIP, enrich the understanding of the essential molecular mechanism for MIIP inhibiting tumorigenesis and progression, and complement the breast cancer-associated miRNAs.

我们在前期工作中发现迁移侵袭抑制蛋白MIIP能够抑制乳腺癌细胞的增殖和迁移侵袭能力，过表达MIIP可上调miR-8072的表达，而miR-8072对乳腺癌细胞具抑癌作用；结合MIIP蛋白亚细胞定位于细胞浆和细胞核、且在乳腺癌临床组织标本中MIIP的细胞浆定位与乳腺癌的发生具有相关性的研究结果，我们推测，亚细胞定位改变可能影响MIIP的抑癌功能、MIIP可能作为转录因子或转录共调节因子对包括miRNA在内的癌基因或抑癌基因进行表达调控。本项目拟通过一系列研究手段，揭示MIIP对miR-8072的表达调控作用及可能的分子机制，探索乳腺癌中MIIP亚细胞定位改变的机制及功能效应，明确miR-8072在MIIP抑制肿瘤发生发展中的作用和机制，从而拓宽对MIIP功能的认识，丰富对MIIP抑制乳腺癌发生发展分子机制的了解，并补充与乳腺癌发生发展相关的miRNA分子。

乳腺癌是全球范围内女性最常见的恶性肿瘤，也是女性癌症死亡的首要原因。肿瘤复发及耐药性的产生仍是乳腺癌临床治疗面临的难题，进一步深入研究和揭示乳腺癌发生发展的分子机制，有助于发现和确定乳腺癌的新型分子标记和治疗靶点。本研究中，我们通过组织学水平、细胞学水平及体内动物实验三个层次，研究了miR-8072与迁移侵袭抑制蛋白MIIP的表达调控关系，明确并初步揭示了miR-8072在乳腺癌发生发展中的作用和潜在机制。研究结果显示，miR-8072能够抑制乳腺癌细胞的体内外增殖能力及体外迁移侵袭能力；在表达水平上，miR-8072与MIIP蛋白呈现正反馈的调节关系；分子机制上，TFAP2A是miR-8072在乳腺癌中发挥抑癌作用的靶基因；通过对TFAP2A表达的转录后水平负性调节，miR-8072能够抑制乳腺癌细胞的上皮间质转化能力及Hif1α信号通络，从而发挥抗增殖及迁移侵袭能力的作用。本项目的完成丰富了对MIIP抑癌机制的了解，补充了与乳腺癌发生发展相关的miRNA分子，为临床乳腺癌的防治提供了潜在的早期诊断分子标记物和治疗靶点。