Dai Y, Wilson G, Huang B, Peng M, Teng G, Zhang D, Zhang R, Ebert M P A, Chen J, Wong B C Y, Chan K W, George J, Qiao L
Department of Gastroenterology, Peking University First Hospital, Beijing, China.
Storr Liver Unit, Westmead Millennium Institute, Department of Medicine and Western Clinical School, The University of Sydney, Westmead, NSW, Australia.
Cell Death Dis. 2014 Apr 10;5(4):e1170. doi: 10.1038/cddis.2014.137.
Dysregulated Notch signaling has a critical role in the tumorigenesis. Jagged1, a Notch ligand, is overexpressed in various human cancers. Recent studies revealed the involvement of Jagged1 in colorectal cancer (CRC) development. These basic studies provide a promising potential for inhibition of the Notch pathway for the treatment of CRC. Herein, we aimed to investigate the consequences of targeting Jagged1 using shRNA on CRC both in vitro and in vivo to test their potential to inhibit this key element for CRC treatment. We found that downregulation of Jagged1 with lentiviral Jagged1-shRNA resulted in decreased colon cancer cell viability in vitro, most likely mediated through reduced cell proliferation. Importantly, Jagged1 knockdown induced G0/G1 phase cell cycle arrest, with reduced Cyclin D1, Cyclin E and c-Myc expression. Silencing of Jagged1 reduced the migration and invasive capacity of the colon cancer cells in vitro. Furthermore, colon cancer cells with knockdown of Jagged1 had much slower growth rate than control cells in a xenograft mouse model in vivo, with a marked downregulation of cell proliferation markers (PCNA, Ki-67, and c-Myc) and metastasis markers (MMP-2 and MMP-9). These findings rationalize a mechanistic approach to CRC treatment based on Jagged1-targeted therapeutic development.
Notch信号失调在肿瘤发生中起关键作用。Notch配体Jagged1在多种人类癌症中过表达。最近的研究揭示了Jagged1参与结直肠癌（CRC）的发展。这些基础研究为通过抑制Notch信号通路治疗CRC提供了有前景的可能性。在此，我们旨在研究使用shRNA靶向Jagged1对CRC在体外和体内的影响，以测试其抑制CRC治疗这一关键要素的潜力。我们发现，用慢病毒Jagged1-shRNA下调Jagged1会导致体外结肠癌细胞活力降低，这很可能是通过减少细胞增殖介导的。重要的是，Jagged1敲低诱导G0/G1期细胞周期停滞，同时细胞周期蛋白D1、细胞周期蛋白E和c-Myc表达减少。沉默Jagged1降低了体外结肠癌细胞的迁移和侵袭能力。此外，在体内异种移植小鼠模型中，Jagged1敲低的结肠癌细胞生长速度比对照细胞慢得多，细胞增殖标志物（PCNA、Ki-67和c-Myc）和转移标志物（MMP-2和MMP-9）明显下调。这些发现为基于靶向Jagged1的治疗开发的CRC治疗机制方法提供了理论依据。
