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Objective: Endoplasmic reticulum-metallopeptidase 1 (ERMP1) is involved in cellular response to oxidative stress.However, its functional role in proliferation and progression of cancer cells remains unknown. The focus of this studywas to investigate the molecular-mechanisms in which ERMP1 modulates the proliferation and progression of colorectalcancer (CRC) cells under normal and environment stress conditions.Materials and Methods: In this experimental study, ERMP1 expression was evaluated using reverse transcriptionquantitativepolymerase chain reaction (RT-qPCR) in CRC cells. ERMP1 was knocked down using lentiviral transductionof ERMP1-specific shRNA into HCT116 cells. ERMP1 was also upregulated using lipofectamine transfection ofERMP1-overexpressing vector into SW48 cells. To evaluate the role of ERMP1 in the cellular and environmental stressconditions, ERMP1-downregulated cells were exposed to stressful conditions including starvation, serum free medium,and treatment with redox or chemotherapy agents for 72 hours. The expression of AKT, p-AKT, phospho-mammaliantarget of rapamycin (p-mTOR), β-catenin, p-β-catenin, E-cadherin, and Glucose-regulating protein 78 (GRP78) proteinswas evaluated by western blotting. The expression of ERMP1, CYCLIN D, and c-MYC was evaluated by RT-qPCR. Thecell surface localization of GRP78, cell cycle distribution, and apoptosis were determined by Flow cytometry.Results: ERMP1 knock-down reduced the cellular proliferation, inactivated the PI3K/AKT pathway, prompted theG1 arrest, and attenuated the free β-catenin and CYCLIN D expression. Opposite results were obtained in ERMP1-overexpressed cells. Knock-down of ERMP1 also reduced the GRP78 localization at the cell surface. Variousenvironmental stress conditions differently affected the ERMP1-downregulated cells.Conclusion: ERMP1 functioned as an oncogene in CRC cells by promoting malignant characteristics. Thephosphoinositide 3-kinases (PI3K)/AKT/β-catenin pathway and localization of GRP78 were closely related to the effectsof ERMP1. Consequently, ERMP1 might be regarded as a promising target in therapeutic strategies related to CRC.