长链非编码RNA n409101调控Numb/Notch信号通路介导前列腺癌干细胞干性维持的机制研究

The existence of cancer stem cells is a major cause of metastasis, relapse and therapy-resistance for malignancy. Targeting cancer stem cells is is a key to cure cancer, however the regulatory mechanism of which has not yet been fully elucidated. In recent years, growing evidence demonstrates that long noncoding RNA（lncRNA）play important regulatory role in growth and proliferation of tumor cells, But its role in the stemness maintenance and biological behavior of prostate cancer stem cell（PCSC）is still unclear. Our previous studies showed that the expression level of lncRNA-n409101 was increased in PCSC, downregulation of lncRNA-n409101 impaired PCSC xenograft tumor regeneration in vivo and self-renewal ability in vitro. The further bioinformatics prediction and western bolt analysis showed that Numb in Noth signaling pathway, one of its nearby genes, might be a potential key target of it. Therefore, we hypothesize that lncRNA-n409101 mediate the stemness of PCSC via regulating Numb/Notch signaling pathway. This study intends to certify that lncRNA-n409101 may promote the development and progression of PCa by PCSC by small interfering RNA in vitro and vivo, and investigate the molecular mechanisms behind this process, which will provide new intervention target in the clinical treatment of targeting PCSC.

肿瘤干细胞是导致恶性肿瘤转移、复发和耐药的根源，目前已成为肿瘤靶向治疗的关键，但其调控机制至今尚未完全阐明。近年研究表明，长链非编码RNA（lncRNA）对肿瘤细胞的增殖和生长具有重要的调控作用，但对前列腺癌干细胞（PCSC）干性维持及生物学行为的作用机制尚待研究。我们前期研究发现lncRNA-n409101在PCSC中表达显著上调，下调其表达可影响PCSC的成瘤能力和自我更新能力。后续的生物信息学和蛋白质免疫印迹分析表明Notch信号通路的Numb基因可能是其潜在的作用位点。因此，我们提出假说：lncRNA-n409101通过调控Numb/Notch信号通路介导PCSC的干性维持。本项目拟利用小干扰RNA技术通过体内外实验对该假说加以验证，进而从lncRNA的角度深入阐明PCSC参与前列腺癌发生发展的分子机制，同时也可为临床靶向PCSC的治疗提供新的干预靶点和举措。

前列腺癌是男性高发的恶性肿瘤，其调控机制复杂，其中肿瘤干细胞的调控机制尤其需要进一步的研究和探讨。我们发现lncRNA n409101在CD44+ PCSC中表达显著上调，下调其表达可影响前列腺癌细胞的生长能力和侵袭能力，干扰肿瘤干细胞的成瘤能力和自我更新能力。Numb在前列腺癌细胞及前列腺癌肿瘤干细胞中发挥着相反的功能。生物信息学和蛋白质免疫印迹分析及rescue assay表明Notch信号通路的Numb基因是lncRNA的下游调控基因。这为前列腺癌细胞的治疗提供了新的思路和潜在的治疗靶点。