Knockdown of IRE1α inhibits colonic tumorigenesis through decreasing β-catenin and IRE1α targeting suppresses colon cancer cells
| Autor: | li（范莉） Fan, Yanqing Qin, Jiye Fang, Ruifen Zhang, Xia Li, Yuhai Chen, Haicheng Zhang, Yi Liu, Yonghua Xu, Min Li |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Cancer Research Carcinogenesis Colorectal cancer Mice Nude Protein Serine-Threonine Kinases Biology medicine.disease_cause 03 medical and health sciences Cell Line Tumor Endoribonucleases Genetics medicine Animals Humans Molecular Biology beta Catenin Cell Proliferation Mice Knockout Gene knockdown Endoplasmic reticulum Colitis medicine.disease Molecular biology Tumor Burden Mice Inbred C57BL HEK293 Cells 030104 developmental biology Gene Knockdown Techniques Catenin Colonic Neoplasms Neoplastic Stem Cells Unfolded protein response Cancer research Stem cell Signal transduction Neoplasm Transplantation Signal Transduction |
| Zdroj: | Oncogene. 36:6738-6746 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2017.284 |
| Popis: | The endoplasmic reticulum (ER) stress occurs frequently in cancers. The unfolded protein response (UPR) is activated to cope with ER stress. This has generated widespread interest in targeting UPR as therapeutic strategies. Inositol-requiring transmembrane kinase/endonuclease 1α (IRE1α), an ER stress sensor, is a key component of UPR. However, the role of IRE1α in tumorigenesis remains unclear. The purpose of this work is to investigate the role of IRE1α in colon cancer and to determine whether IRE1α could serve as a target for therapy. We found that knockdown of IRE1α suppressed the proliferation of colon cancer cells in vitro and xenograft growth in vivo. Inhibition of expression of IRE1α decreased stemness of colon cancer stem cells (CSCs) and attenuated growth of intestinal organoids. Genetic ablation of IRE1α prevented the colitis-associated colonic tumorigenesis in mice. The mechanistic study indicates that knockdown of IRE1α repressed the expression of β-catenin, a key factor that drives colonic tumorigenesis, through activating pancreatic ER kinase/eukaryotic translation initiation factor 2α signaling. We found that the IRE1a-specific inhibitor 4μ8C could suppress the production of β-catenin, inhibited the proliferation of colon cancer cells, repressed colon CSCs and prevented xenograft growth. The results suggest that IRE1α has a critical role in colonic tumorigenesis and IRE1α targeting might be a strategy for treatment of colon cancers. |
| Databáze: | OpenAIRE |
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