MAGEA6 Influences Chemosensitivity Of Cisplatin In ESCC By Regulating Caspase-1-mediated Pyroptosis

BackgroundChina is a country with a high incidence of esophageal cancer,especially esophageal squamous cell carcinoma(ESCC).Chemoresistance is the main cause of poor prognosis in patients with advanced ESCC,and cisplatin is a classic chemotherapy drug for ESCC.As a result,improving chemosensitivity of cisplatin is a key to treat it.Reduction of cell death is one of the mechanisms of chemoresistance.Recent studies have shown that some chemotherapeutic drugs can induce pyroptosis.Pyroptosis,as a new type of cell death,may provide new ideas for the research of chemosensitivity.Our earlier research discovered that MAGEA6 has a high expression in chemoresistance ESCC tissues.In this study,we aim to investigate the effect of MAGEA6 on chemosensitivity of cisplatin in ESCC cells,and clear the relationship between MAGEA6 and pyroptosis,in hope to find the theoretical basis for potential therapeutic targets in esophageal squamous cancer.MethodsFirst of all,MAGEA6 expression in ESCC is analyzed by the TCGA database and tested from clinical tissue samples.Then CCK8 assay was performed to assess the effect of MAGEA6 expression on chemosensitivity of cisplatin in ESCC cells.Lentivirus was transfected to knock-down the expression of MAGEA6 in ESCC cells.Then,by performing the CCK8 assay,observing the cell morphology and the Western blot to confirm the relationship between MAGEA6 and pyroptosis.Next step,we take the Western blot,qRT-PCR and dual luciferase assay to clarify the mechanism of MAGEA6 on pyroptosis.Finally,subcutaneous xenotrans planted tumor model in nude mice were established,which verified the effect of MAGEA6 on chemosensitivity of cisplatin in vivo.Results1.MAGEA6 is highly expressed in ESCC tissues,especially in chemoresistance ESCC;2.MAGEA6 is highly expressed and affects chemosensitivity of cisplatin in ESCC cells;3.Knockdown of MAGEA6 can improve chemosensitivity of cisplatin by inducing pyroptosis in ESCC cells;4.MAGEA6 suppressed pyroptosis via inhibiting transcriptional activity of Caspase-1.5.Animal experiments confirmed that knockdown of MAGEA6 expression can improve chemosensitivity of cisplatin in ESCC.ConclusionsMAGEA6 is highly expressed in ESCC and inhibits pyroptosis by reducing the transcriptional activity of Caspase-1,which ultimately leads to chemoresistance of cisplatin.