For instance, in non-small cell lung cancer, NOTCH1 activates a positive feedback loop with its downstream target RFC4, promoting metastasis and stemness traits in tumor cells.20 In hepatocellular carcinoma, NOTCH1 drives EMT and metastasis through the RNF187 activation.21 However, the role of Notch signaling in ESCC remains controversial, with studies reporting divergent effects depending on the stage and context of the cancer. This evidence concerns the gene RFC4 and cancer.