IGF1/IGF1R/STAT3 Signaling-inducible IFITM2 Promotes Gastric Cancer Growth And Metastasis

Background and purposeGastric cancer(GC)remains one of the commonest causes of cancer mortality worldwide,especially in China.Up to 20%of patients receive gastric resection in curative intent if the gastric cancer is detected at an early stage.Unfortunately,gastric cancer is often diagnosed at an advanced stage with poor prognosis,when only palliative treatment can be considered.Invasion and metastasis is considered as one of the main factors of poor prognosis in patients with gastric cancer,but its specific mechanism is not clear.Therefore,it is very important to explore the relevant mechanism and find new prognostic molecules and therapeutic targets of gastric cancer.Recent studies have demonstrated that epithelial-mesenchymal transition(EMT)is one of the beginning steps in invasion and metastasis of all kinds of epithelial-derived malignancies.Many factors can induce the occurrence of EMT,but the specific mechanism is not clear.It is believed that EMT is an important model of the response of tumor cells to the various stimuli of tumor microenvironment(TME)during tumor progression.When gastric cancer cells receive signal from multiple growth factors in the TME,tumor cells lose cell-to-cell connectivity,gain the potential for migration and infiltration,and promote tumor progression.Insulin-like growth factor 1(IGF1)axis that has been reported to facilitate gastric carcinogenesis,and to increase the metastatic potential of gastric cancer cells.However,the specific mechanisms by which IGF1 signaling pathways play a malignant biological function in gastric cancer are not fully elucidated.Interferon-induced transmembrane protein 2(IFITM2),also known as 1-8D,belongs to IFN-inducible transmembrane proteins(IFITMs).The family also includes IFITM1(9-27)and IFITM3(1-8U),located on the 18kp fragment of human chromosome 11,with high homology among family members.At present,the family's research focused on its antiviral effect,and its research in the field of cancer is still in its infancy,especially IFITM2 is rarely reported.In recent years,a number of studies have found that IFITM1,IFITM3 can promote the migration and invasion of gastric cancer cells by mediating the EMT process.However,there is little research on IFITM2,especially its role in gastric cancer has not been reported.Therefore,this study is to explore the role of IFITM2 in gastric cancer,to determine whether it can regulate EMT to promote gastric cancer invasion and metastasis,and whether IGF1 can induce IFITM2-mediated invasion and metastasis of gastric cancer.This study lays a foundation for elucidating the specific mechanism of IFITM2 in promoting the growth and metastasis of gastric cancer and provides a new way for the subsequent development of targeted targets for gastric cancer targeted therapy.MethodsIn this study,the expression of IFITM2 in gastric cancer samples was analyzed by bioinformatics(TCGA),Western Blot(WB)and immunohistochemical staining.Molecular and cellular techniques including siRNA-mediated and lentiviral vector-mediated knockdown were used to elucidate the functions and mechanisms of IFITM2 in vivo and vitro.ResultIn this study,we demonstrated for the first time that(?)IFITM2 expression is highly expressed in GC;(?)IFITM2 elevation is associated with an advanced disease,a higher incidence of recurrence and a shorter survival time;(?)IFITM2 contributes to tumor cell proliferation,invasion,migration,EMT and xenograft tumor growth and metastasis;(?)IFITM2 is also confirmed to be involved in IGF1/IGF1R/STAT3 pathway and IL-6 secretion.ConclusionIGF1/IGF1R/STAT3 signaling-inducible IFITM2 promotes gastric cancer growth and metastasis.