Study Of The Mechanism On The Stabilization Of YAP By TAK1 Regulates The Self-renewal And Oncogenesis Of Gastric Cancer Stem Cells

Background: Gastric cancer(GC)is the most common malignant tumor of the digestive system and the third leading cause of cancer deaths worldwide.Cancer stem cells(CSCs)as a small subset of cancer cells in solid tumors with the self-renewal,differentiation and tumorigenic ability are responsible for tumor initiation,progression,recurrence,metastasis,and resistance to chemotherapy and radiotherapy.Gastric cancer stem cells have been identified and shown to correlate with gastric cancer initiation and metastasis.The objective of this study is to evaluate the role of TGFβ-activated kinase 1(TAK1)in self-renewal and tumorigenesis of gastric cancer stem cells(GCSCs).Methods: The expression of TAK1 in GC was evaluated by RT-q PCR,western bolt and immunohistochemistry.The effects of TAK1 on the malignant phenotype of GC were evaluated through various cell function experiments in vivo and in vitro.We induced the MKN45 and MGC803 cell lines to form stem cell microspheres by conditioned culture.We have clarified the self-renewal ability of stem cells through microsphere formation and flow analysis.Mass spectrometry analysis,Co-IP analysis and immunofluorescence are used to understand the combination of TAK1 and YAP.At the same time,we understand the protein expression levels of upstream and downstream related molecules through western blot.In addition,we also explored the therapeutic effect of targeting TAK1 on gastric cancer in vivo and in vitro.Results: We found that the expression level of TAK1 in GC tissue was significantly higher than that in adjacent tissues.TAK1 can promote a variety of malignant phenotypes of gastric cancer in vivo and in vitro,and promote the self-renewal of gastric cancer stem cells.In terms of mechanism,TAK1 occupies the Ser127 residue site of YAP in a nonkinase active form,thereby preventing it from being phosphorylated and degraded by upstream LATS1/2,inducing nuclear translocation of YAP,promoting the expression of downstream transcription factors SOX2 and SOX9,and ultimately promoting the selfrenewal ability of gastric cancer stem cells.The IL-6 secreted by tumor-associated fibroblasts in the tumor microenvironment of gastric cancer promotes the expression of TAK1 and further enhances its ability to promote the progression of gastric cancer.Targeting TAK1 can increase the chemotherapy sensitivity of gastric cancer cells.Conclusion: TAK1 can regulate the self-renewal and tumorigenesis of gastric cancer stem cells.Targeting TAK1 may be a potential therapeutic target for clinical intervention in gastric cancer.