RESUMO
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multifunctional hematopoietic growth factor that can promote the recovery of leukopenia caused by tumor chemoradiotherapy, and can also prevent chemoradiotherapy-induced mucositis by promoting a variety of cells such as endothelial cells, epithelial cells, keratinocytes and fibroblasts. This article reviews the domestic and foreign basic and clinical research progress of GM-CSF in recent years, and discusses the mechanism and clinical application of GM-CSF as a mucosal repair agent in the prevention and treatment of tumor chemoradiotherapy-induced mucositis.
RESUMO
OBJECTIVES@#Ulcerative colitis (UC) is a chronic, relapsing inflammation of the colon. Impaired epithelial repair is an important biological features of UC. Accelerating intestinal epithelial repair to achieve endoscopic mucosal healing has become a key goal in UC. Yes-associated protein (YAP) is a key transcriptional coactivator that regulates organ size, tissue growth and tumorigenesis. Growing studies have focused on the role of YAP in intestinal epithelial regeneration. This study explore the molecular mechanism for the role YAP in modulating colonic epithelial proliferation, repair, and the development of colitis associated cancer.@*METHODS@#We constructed the acute colitis mouse model through successive 5 days of 3% dextran sulfate sodium salt (DSS) induction. Then YAP-overexpressed mouse model was constructed by intraperitoneal injection the YAP overexpressed and negative control lentivirus into DSS mice. On the 5th day of DSS induction and the 5th day of normal drinking water after removing DSS (5+5 d), the mice were killed by spinal dislocation. The colon was taken to measure the length, and the bowel 1-2 cm near the anal canal was selected for immunohistochemical and Western blotting. We used YAP over-expressed colonic epithelial cells and small interfering signal transducer and activator of transcription 3 (STAT3) RNA to probe the regulation of YAP on STAT3, using cell counting kit-8 and scratch assays to explore the role of YAP on colonic epithelial cell proliferation. Finally, we conducted co-immunoprecipitation to test the relationship between YAP and STAT3.@*RESULTS@#After DSS treatment, the expression of YAP was dramatically diminished in crypts. Compared with the empty control mice, overexpression of YAP drastically accelerated epithelial regeneration after DSS induced colitis, presenting with more intact of structural integrity in intestinal epithelium and a reduction in the number of inflammatory cells in the mucosa. Further Western blotting, functional experiment and co-immunoprecipitation analyses showed that the expression of YAP in nucleus was significantly increased by 2 h post DSS cessation, accompanied with up-regulated total protein levels of STAT3 and phosphorylated-STAT3 (p-STAT3). Overexpression of YAP enhanced the expression of STAT3, p-STAT3, and their transcriptional targets including c-Myc and Cyclin D1. In addition, it promoted the proliferation and the "wound healing" of colonic cells. However, these effects were reversed when silencing STAT3 on YAP-overexpressed FHC cells. Moreover, protein immunoprecipitation indicated that YAP could directly interact with STAT3 in the nucleus, up-regulatvng the expressvon of STAT3. Finally, during the process of CAC, overexpression of YAP mutant caused the down-regulated expression of STAT3 and inhibited the development and progress of CAC.@*CONCLUSIONS@#YAP activates STAT3 signaling in regulation of epithelial cell proliferation and promotes mucosal regeneration after DSS induced colitis, which may serve as a potential therapeutic target in UC. However, persistent and excessive YAP activation may promote CAC development.
Assuntos
Animais , Camundongos , Proliferação de Células , Colite/tratamento farmacológico , Colo/metabolismo , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Mucosa Intestinal , Camundongos Endogâmicos C57BL , Recidiva Local de Neoplasia/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteínas de Sinalização YAP/metabolismoRESUMO
The defense and repair function of the gastrointestinal mucosa is of great significance for protecting the integrity of mucosa. A large number of studies have shown that the defense and repair system of gastrointestinal mucosa is a three-dimensional network system, and gut hormones participate in the whole process, thereby playing an important role for diseases related to mucosal injury. This article reviewed the roles of gut hormones in mucosal defense and repair.