细胞命运决定子Numb/Numblike在前列腺细胞对称不对称分裂、谱系分化及肿瘤发生中的作用机制研究

前列腺癌是严重威胁男性健康的恶性肿瘤。前列腺细胞扩增及分化异常是导致前列腺癌生成的可能重要因素，前列腺肿瘤干细胞又是前列腺癌恶化复发的可能元凶。我们的前期基础和预实验发现：①细胞命运决定子Numb与人类前列腺肿瘤的进展恶化呈负相关,小鼠中敲除Numb/Numblike的敲除后产生前列腺上皮内瘤；②正常的前列腺基底细胞和hTERT高表达的前列腺肿瘤干细胞均可进行对称和不对称分裂，Numb在其不对称分裂中特异性的分布于分化的细胞中；④Numb通过下调Notch和Hedgehog通路活性起抑制肿瘤的作用。我们将利用基因敲除小鼠、前列腺肿瘤干细胞荧光报告细胞系和病人样本，研究Numb/Numblike缺失后对正常前列腺细胞和前列腺肿瘤干细胞的分裂模式及细胞谱系分化的影响，力图从干细胞生物学的角度阐明前列腺癌发生的机理及前列腺肿瘤干细胞扩增的机制，为临床治疗提供新的线索和靶标。

Prostate cancer is one of the most frequent types of cancer and leading causes of death in males. Our preliminary results indicate that （1) the evolutionary conserved cell fate determinant Numb is significantly negatively associated with prostatic tumor progression. Deletion of Numb/Numblike in a mouse model leads to prostatic intraepithelial neoplasia. (2) Progenitor cells in prostatic basal cell compartment and hTERT highly expressed prostate tumor stem cells undergo symmetric and asymmetric cell divisions. Numb is asymmetric distributed to the differentiated daughter cell during asymmetric division. (3) Numb exerts a prostatic tumor suppression effect via downregulation of the Notch and Hedgehog signal pathways. We will investigate whether and how Numb/Numblike affect prostatic cell polarity, cell division mode and differentiation using gene deletion mouse models, the hTERT promoter tumor stem cell reporter cell line, and patient samples. This study will provide new insight into the mechanism of prostate tumorigenesis and expansion of tumor stem cells from the angle of stem cell biology.