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Weiyi Dong,1,* Zheng Cao,2,* Yanmin Pang,3 Teng Feng,1 Hongtao Tian1 1Department of Pathology, Heze Municipal Hospital, Heze City, Shandong 274031, People’s Republic of China; 2Department of Pathology, Juye County People’s Hospital, Heze City, Shandong 274900, People’s Republic of China; 3Department of Intensive Care Unit, Heze Municipal Hospital, Heze City, Shandong 274031, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongtao TianDepartment of Pathology, Heze Municipal Hospital, No. 2888, Caozhou West Road, Heze City, Shandong 274031, People’s Republic of ChinaTel +86 15553007892Fax +86 05305613311Email tianhongtao2011@163.comIntroduction: The role of CARF, a calcium-responsive transcription factor, in colorectal cancer initiation and development is still unknown. Here, we report that CARF promotes colorectal cancer stemness through ERBB signaling pathway.Materials and methods: Both colorectal cancer cell lines and primary cells were used in this study. The levels of target mRNA and protein in the cells were examined by qRT-PCR and Western blot. Gene manipulation was achieved by the lentivirus delivery system. Luciferase reporter gene assay was employed to analyze the transcriptional activity of the promoter. ChIP assay was performed for the examination of the binding between CARF and the promoters of MAPK8 and JUN. Kaplan-Meier survival curve was generated by the R2 program. Correlation analysis was performed using Spearman correlation analysis.Results: Aberrant upregulation of CARF has been found in tumor tissues of colorectal cancer patients and associated with poor prognosis. Ectopic expression of CARF promoted the sphere-formation activities, as well as the expression of stem cell markers in colorectal cancer cells and knockdown of CARF, inhibited these activities. The mechanistic analysis showed that CARF directly binds to the promoter of MAPK8 and JUN, promotes the expression of MAPK8 and JUN, activates the ERBB signaling pathway, and thereby promotes the maintenance of the stemness in colorectal cancer cells.Conclusion: CARF, as an oncogene, promotes colorectal cancer stemness by activating ERBB signaling pathway. The ERBB signaling pathway that serves as the main downstream effector of CARF could be an efficient drug target for colorectal cancer caused by aberrant expression of CARF.Keywords: CARF, colorectal cancer, stemness, ERBB signaling, JUN