Upregulation of miR-665 promotes apoptosis and colitis in inflammatory bowel disease by repressing the endoplasmic reticulum stress components XBP1 and ORMDL3.
MicroRNAs are critical post-transcriptional regulators of gene expression and key mediators of pathophysiology of inflammatory bowel disease (IBD). This study is aimed to study the role of miR-665 in the progression of IBD. Real-time PCR analysis was used to determine miR-665 expression in 89 freshly isolated IBD samples and dextran sulfate sodium (DSS)-induced colonic mucosal tissues. The role of miR-665 in inducing apoptosis and colitis were examined by Annexin V, TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) staining, colony formation in vitro and DSS-induced colitis mice model in vivo. Moreover, luciferase reporter assay, western blot analysis and microribonucleoprotein immunoprecipitation were performed to determine that miR-665 directly repressed XBP1 (X-box-binding protein-1) and ORMDL3 expression. Herein, our results revealed that miR-665 was markedly upregulated in active colitis. Gain-of-function and loss-of-function studies showed that ectopic expression of miR-665 promoted apoptosis under different inflammatory stimuli. Importantly, delivery of miR-665 mimic promoted, while injection of antagomiR-665 markedly impaired DSS-induced colitis in vivo. Mechanistically, we demonstrated that miR-665 induced apoptosis by inhibiting XBP1 and ORMDL3. Taken together, our findings reveal a new regulatory mechanism for ER stress signaling and suggest that miR-665 might be a potential target in IBD therapy.
Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People's Republic of China.
Manying
M
Li
Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People's Republic of China.
Shenghong
S
Zhang
Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People's Republic of China.
Yun
Y
Qiu
Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People's Republic of China.
Yao
Y
He
Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People's Republic of China.
Baili
B
Chen
Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People's Republic of China.
Ren
R
Mao
Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People's Republic of China.
Yi
Y
Cui
Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People's Republic of China.
Zhirong
Z
Zeng
Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People's Republic of China.
Minhu
M
Chen
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003106:Colon; D016264:Dextran Sulfate / Q000494:pharmacology; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D019073:HT29 Cells; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics*; D000071717:X-Box Binding Protein 1 / Q000378:metabolism*
C000592932:MIRN665 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C464399:ORMDL3 protein, human; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D016264:Dextran Sulfate