| Background: Gastric cancer(GC)is a kind of malignant tumor derived from digestive system that poses a serious threat to human health.It has become the second leading cause of cancer death in the world.Surgery,in combination with chemotherapy,is the most promising therapeutic strategy against advanced GC.However,with the progressive chemoresistance of gastric cancer cells,refractory GC has been more and more common.In recent years,molecular targeted therapy has become a new method for the treatment of advanced GC due to its mild adverse reactions,low drug resistance rate and better therapeutic effect.In GC,recent studies showed that the expression of DEC2 in carcinoma tissue was low as compared with that in paracarcinoma tissue and overexpression of DEC2 induced better prognosis by inhibiting proliferation,migration,invasion,EMT and promoting apoptosis of GC cells,but the effect of DEC2 on chemosensitivity of GC cells is still unclear up to now.As two important members of Signal transducers and activators of transcription(STAT)protein family,activation of STAT3 and STAT5(STAT5A,STAT5B)by phosphorylation plays crucial roles in both inducing JAUNS kinase/STAT signaling pathway and mediating tumorigenesis.Moreover,It was also revealed that the chemosensitivity of many kinds of cancer cells could be weakened by the activation of STAT3 and STAT5 including GC.5-Fluorouracil(5-Fu)is one of the first-line chemotherapy drugs for advanced GC.In the face of the increasing chemoresistance rate of gastric cancer cells,the effects of DEC2 on the chemosensitivity of GC cells to 5-Fu-based chemotherapy has not been reported,and the role of DEC2 involved in regulating the expression of STAT proteins is currently unclear.Objective: In the present study,we aimed to find the effect of DEC2 on the chemosensitivity associated with GC and related signaling pathways,to study the correlation between expression of DEC2 and STAT3 or STAT5 in GC tissues and the mechanism of interaction,to explore the relevant signaling pathway for regulating the chemosensitivity of GC cells,to provide new clinical ideas for reversing the drug resistance and for the future molecular targeted therapy of GC.Methods: The GC cell lines stably overexpressing DEC2 was obtained by lentiviral transfection technique.After treatment with 5-Fu,the effects of DEC2 overexpression on cell proliferation and apoptosis were evaluated using Cell Counting Kit-8(CCK-8)assay,5-ethynyl-2'-deox-yuridine(EdU)assay and flow cytometry experiment.Western blot analysis was performed to assess the influences of DEC2 overexpression on apoptosis-related proteins and STAT molecules.Further,expressions of DEC2 and STAT proteins were evaluated by IHC analysis through 88 GC and corresponding paracarcinoma clinical specimens.Spearman's correlation analysis and Kaplan-Meier survival analysis were conducted to determine the correlation of DEC2 and STAT proteins and the significance of this two kinds of molecules to the prognosis associated with GC patients.Finally,simultaneous overexpression of DEC2 and STAT5 A in one cell were established to detect the effects of STAT proteins overexpression on DEC2-induced enhanced chemosensitivityResults:1.Expression of DEC2 increases sensibility of MKN45 and MKN28 GC cells to 5-Fu.2.DEC2 enhances chemosensitivity through regulating apoptosis-related proteins.3.DEC2 induces downregulation of P-STAT5 A significantly but has no regulatory significance for the activation of STAT3 and STAT5 B in MKN45 and MKN28 GC cells.4.High level of P-STAT5 A expression is negatively correlated with DEC2 expression as well as with poor patient survival in GC.5.Enhanced chemosensitivity of GC cells mediated by DEC2 could be reversed by STAT5 A.Conclusion:1.Overexpression of DEC2 is identified to enhance chemosensitivity of GC cells.2.DEC2 inhibits the phosphorylation of STAT5 A,which accounts for enhanced chemosensitivity of GC cells.3.DEC2/STAT5 A signaling pathway has important guiding significance for chemosensitivity and clinical prognosis of patients with GC. |
PDF Full Text Request