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Objective: Solute carrier family 38 (SLC38s) transporters play important roles in amino acid transportation and signaling transduction.However,their generic alterations and biological roles in tumors are still largely unclear.This study aimed to elucidate the genetic signatures of SLC38s uransporters and their implications in esophageal squamous cell carcinoma (ESCC).Methods: Analyses on somatic mutation and copy number alterations (CNAs) of SLC38A3 were performed as described.Immunohistochemistry (IHC) assay and Western blot assay were used to detect the protein expression level.MTS assay,colony formation assay,transwell assay and wound healing assay were used to explore the malignant phenotypes of ESCC cells.Immunofluorescence assay was used to verify the colocalization of two indicated proteins and immunopreciptation assay was performed to confirm the interaction of proteins.Results: Our findings revealed that SLC38s family was significantly disrupted in ESCC,with high frequent CNAs and few somatic mutations.SLC38A3 was the most frequent loss gene among them and was linked to poor survival and lymph node metastasis.The expression of SLC38A3 was lower in tumor tissues compared to that in normal tissues,which was also significantly associated with worse clinical outcome.Further experiments revealed that depletion of SLC38A3 could promote EMT in ESCC cell lines,and the interaction of SLC38A3 and SETDB1 might lead to the reduced transcription of Snail.Pharmacogenomic analyses demonstrated that fifteen inhibitors were showed significantly correlated with SLC38A3 expression.Conclusions: Our investigations have provided insights that SLC38A3 could act as a suppressor in EMT pathway and serve as a prognostic factor and predictor of differential drug sensitivities in ESCC.