Functions And Mechanisms Of Crosstalk Between STAT3 And FGFR4 In The Drug Resistance Of Hepatocellular Carcinoma

At present,hepatocellular Carcinoma(HCC)has become one of the most common malignant tumors in China.The prevalence of risk factors in China leads to a very high incidence of HCC and its low differentiation makes HCC a serious threat to people’s lives.Currently,chemotherapy and hepatectomy are the main treatments for HCC,and Sorafenib and Lenvatinib are among approved drugs for systemic treatment,However,short survival time and high drug resistance are found in HCC,there is an urgent need to develop new therapies targeting specific pathways of HCC and to determine better treatment options.It has been reported that signal transducer and activator of transcription3(STAT3)are over-activated in HCC cells and play a key role in the occurrence,development and metastasis of HCC.STAT3,as a key regulator,has been proved to be an ideal target for molecular targeted therapy of HCC and has outstanding therapeutic effect.However,late-stage data of clinical trials show secondary drug resistance and other problems.Therefore,to explore the specific molecular mechanism of STAT3 inhibitor resistance is of great significance and clinical value in the treatment of hepatocellular carcinoma.This project will clarify the mechanism at the clinical and cellular level,and detect the differentially expressed proteins in the culture supernatant of hepatoma cells which inhibit STAT3 expression by antibody chip.The differential expression of fibroblast growth factor receptor 4(FGFR4)in STAT3-resistant cells is compared by Western blotting(WB).The inhibitory effects of STAT3 inhibitor and FGFR4 inhibitor on cell activity are examined by MTT,The effects of STAT3 inhibitors on the expression of P-STAT3/STAT3,FGF19,P-FGFR4/FGFR4 signaling pathway and downstream P-AKT/AKT are examined by WB,The combined effects of two inhibitors on cell proliferation,apoptosis and migration are examined by clonal assay,immunofluorescence staining,Edu cell proliferation detection,hoechst 33342 staining,cell apoptosis assay and migration Assay,the mechanism of drug resistance is further explored by WB.In HCC,STAT3 inhibitor Napabucasin has a good inhibitory effect and can induce the expression of FGF19,P-FGFR4,FGFR4 and their downstream P-AKT and AKT signaling pathways after STAT3 inhibition.In addition,the combination of STAT3 and FGFR4 inhibitors inhibits cell growth and proliferation,promotes cell apoptosis,and inhibits cell migration and metastasis.Inhibition of STAT3 induces the expression of FGF19 and the activation of FGFR4 and its downstream signaling pathways are the key mechanisms of STAT3 inhibitor resistance in hepatocellular carcinoma.Dual inhibitors of STAT3 and FGFR4 may be an effective strategy in the treatment of HCC.The double inhibition of STAT3 and FGFR4 may be an effective strategy in the treatment of HCC.This article will present important ideas in exploring the etiology and drug resistance mechanisms of HCC and new targeted therapies for prevention and treatment.