Silencing of Jagged1 inhibits cell growth and invasion in colorectal cancer.
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.
Department of Gastroenterology, Peking University First Hospital, Beijing, China.
Y
Y
Dai
Storr Liver Unit, Westmead Millennium Institute, Department of Medicine and Western Clinical School, The University of Sydney, Westmead, NSW, Australia.
G
G
Wilson
Research Center of Basic Medical Sciences and Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China.
B
B
Huang
Research Center of Basic Medical Sciences and Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China.
M
M
Peng
Department of Gastroenterology, Peking University First Hospital, Beijing, China.
G
G
Teng
Research Center of Basic Medical Sciences and Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China.
D
D
Zhang
Research Center of Basic Medical Sciences and Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China.
R
R
Zhang
Department of Medicine II, Klinikum Rechts der Isar, Technical University, Munich, Germany.
M P A
MP
Ebert
School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.
J
J
Chen
Departments of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
B C Y
BC
Wong
Departments of Pathology, The University of Hong Kong, Pokfulam, Hong Kong.
K W
KW
Chan
Storr Liver Unit, Westmead Millennium Institute, Department of Medicine and Western Clinical School, The University of Sydney, Westmead, NSW, Australia.
J
J
George
Storr Liver Unit, Westmead Millennium Institute, Department of Medicine and Western Clinical School, The University of Sydney, Westmead, NSW, Australia.
L
L
Qiao
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D015536:Down-Regulation; D059585:G1 Phase Cell Cycle Checkpoints; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins