Research On The Reciprocal Regulatory Mechanism Between MiR-214-3p And FGFR1 In FGFR1 Amplified Lung Cancer

Introduction and Objective:The dysregulation of Fibroblast growth factor receptor 1(FGFR1)plays a very important role in the proliferation,metastasis and the stemness process of tumor.However,the target therapy in clinical trials for FGFR1 inhibitors have shown modest response.Meanwhile,the interaction of miRNA and FGFR1 in in FGFR1 amplified lung cancer has not been reported so far.Therefore,it is important and urgent to explore the mechanism between miRNA and FGFR1 in lung cancer.Methods: First,qRT-PCR was performed to detect the expression levels of 10 miRNAs associated with metastases in lung cancer tissues and adjacent normal tissues of lung cancer.Second,H1581 and DMS114 cells as FGFR1 amplified cell lines were used for the following experiments.After transfection with miRNA mimic or inhibitor,the proliferation was determined by the cck8 assay and clony assay,and the migration and invasion was determined by transwell assay.The protein and RNA were also used for experiments such as western blot and PCR,with the aim of detecting representative markers of epithelial-mesenchymal transition and related signaling pathway molecules.We also established subcutaneous tumor mouse models and orthtopic lung cancer mouse models to further explore the effects of miR-214-3p on invasion and metastasis.The direct target of miR-214-3p were searched by several public databases,including miRwalk,miRBase,Tragetscan,etc,and identified by luciferase reporter assay.Results: We examined the expression levels of 10 miRNAs associated with metastasis in clinical lung carcinoma samples.Among these samples,miR-214-3p was significantly decreased and showed a significant negative correlation with FGFR1.We then confirmed that miR-214-3p could downregulate FGFR1 by directly targeting 3'-UTR with luciferase reporter assay.miR-214-3p inhibited the processes of EMT and wnt/MAPK/PI3/AKT signaling pathway by targeting FGFR1 in FGFR1-amplified cell lines.Moreover,miR-214-3p could not only establish a negative feedback regulation loop with FGFR1 through ERK and but also develop a synergism with FGFR1 inhibitor AZD4547.Conclusion: In summary,we demonstrated that miR-214-3p could be a prognostic factor and a potential biotherapeutic target as a tumor suppressor in FGFR1 amplified lung cancer.Co-targeting miR-214 and FGFR1 may provide greater benefits to patients with FGFR1 amplified lung cancer.