丝裂原活化蛋白激酶磷酸酶-1（MKP-1）去泛素化酶促进乳腺癌化疗耐药的研究

Breast cancer is one of the most common malignancies among females in China. Currently, chemotherapy is a standard strategy to treat breast cancer. However, chemoresistance largely restricts the efficacy of chemotherapy and the survival of patients. As a phosphatase overexpresses in breast cancer， MKP-1(mitogen-activated protein kinase phosphatase-1) promotes breast cancer cell survival and chemoresistance. The MKP-1 protein is quickly degraded via the ubiquitin-proteosome pathway. However, it’s still unknown how MKP-1 is stabilized by deubiquitinases (DUBs). In order to identify the DUBs of MKP-1, we screened a library containing siRNAs that targets 90 DUBs and identify a candidate DUB (B10) for MKP-1. In this study, we will first study how MKP-1 is regulated by B10. Secondly, we will determine whether B10 regulates breast cancer cell survival and chemoresistance through deubiquiting and stabilizing the MKP-1 protein. Thirdly, we will investigate the genetic and expression alterations of B10 in clinical breast cancer samples to explore the possibility that B10 serves as a molecular target for breast cancer diagnosis and treatment. Finally, we will develop a drug screen model aiming at B10 to screen natural compounds which can suppress DUB activity of B10. This study will build a foundation for developing future targeted therapies for chemoresistant breast cancers.

乳腺癌是一种严重危害女性身心健康的常见恶性肿瘤，化疗是治疗乳腺癌的主要方式之一，而耐药是影响乳腺癌患者化疗疗效及生存的主要原因之一。MKP-1已知是一个过量表达在乳腺癌并且促进癌细胞生存和化疗药物抵抗的磷酸酯酶，MKP-1蛋白通过泛素化蛋白酶体通路快速降解，促进其稳定的去泛素化酶目前还没有报道。通过对含有90个去泛素化酶（DUB）siRNA文库进行筛选，我们发现了一个MKP-1的候选DUB（B10），我们将对其进行深入研究：首先，我们将在分子水平分析B10对MKP-1去泛素化调控的机制；然后，我们将在细胞以及动物体内测试B10是否通过稳定MKP-1促进乳腺癌细胞生存和化疗耐药；此外，我们将在乳腺癌临床样本中检测B10的遗传和表达的改变，分析其是否有可能成为乳腺癌诊治的靶标；最后，我们将筛选抑制B10去泛素化酶活性的天然小分子化合物，以期为化疗耐药的乳腺癌诊治奠定基础。

乳腺癌是一种严重危害女性身心健康的常见恶性肿瘤，化疗是治疗乳腺癌的主要方式之一，而耐药是影响乳腺癌患者化疗疗效及生存的主要原因之一。MKP-1已知是一个在乳腺癌过量表达并且促进癌细胞化疗药物抵抗的磷酸酯酶，MKP-1蛋白通过泛素-蛋白酶体通路快速降解，促其稳定的去泛素化酶目前还没有报道。通过对含有90个去泛素化酶（DUB）siRNA文库进行筛选，我们发现了一个MKP-1的候选DUB（B10，即STAMBPL1），我们进一步的研究发现，STAMBPL1通过下调MKP-1蛋白的泛素化水平，在蛋白水平稳定MKP-1的表达；其次，我们证实STAMBPL1通过稳定MKP-1蛋白表达进而抑制JNK信号通路的活化促进乳腺癌细胞对化疗药物的耐受性；最后，我们在乳腺癌细胞系以及临床样本中发现STAMBPL1和MKP-1蛋白表达呈正相关关系，两者的高表达与较差的临床预后相关。这些研究结果提示STAMBPL1/MKP-1可能作为临床乳腺癌的诊治靶标。