ID4 Suppresses Proliferation and Macrophage Polarization in Esophageal Carcinoma through Interaction with TCF4

The poor prognosis of esophageal carcinoma (ESCA) highlights the need to identify novel targets for ESCA treatment. We found that inhibitor of differentiation 4 (ID4) was decreased in ESCA tumor tissues and its expression was associated with the survival of ESCA patients. However, the role of ID4 in ESCA remains unclear. Here, in this study, we found that overexpression of ID4 suppressed the cell proliferation of ESCA in vitro as well as tumor growth in vivo, whereas knockdown of ID4 presented the opposite trend. On the other hand, ESCA cells with overexpression of ID4 reduced macrophage migration and M2 polarization. However, significant increases in macrophage migration and M2 polarization were observed in cultures with ID4 silence. Interestingly, CCL2 was found to mediate the function of ID4 on macrophage polarization. Mechanistically, we identified for the first time that ID4 interacted physically with TCF4 to inactivate TCF4 transcriptional activity, which led to a decrease in CCL2 expression. Moreover, RNA binding protein cell cycle associated protein 1 (CAPRIN1) bound to ID4 mRNA and downregulated its stability, which may contribute to its low expression in ESCA. Taken together, these results support a novel hypothesis that ID4 downregulation may contribute to the development of ESCA by interacting with TCF4, resulting in abnormal proliferation of ESCA cells and tumor-associated macrophage infiltration. ID4 may contribute to the innovation of ESCA biotherapy. Implications: ID4 inhibits ESCA through suppresses cancer cell proliferation and macrophage M2 polarization, and ID4 could be a potential prognostic marker for patients with ESCA.