Abstract
The TP53 gene (encoding the human p53 protein) is mutated in about 50% of non-small cell lung cancer (NSCLC). Loss of p53 is closely related to tumor metastasis and immune regulation, contributing to malignant progression and poor prognosis. However, therapeutic strategies for p53-loss NSCLC are still relatively limited. We found that DPEP2 is a diagnostic marker and predicts better outcome and prognosis in NSCLC with mutant TP53, but not with wild-type TP53. Loss of p53 induced DPEP2 downregulation at cellular and tissue levels. Functionally, DPEP2 inhibited the invasion and migration abilities, and decreased F-actin fibers. Mechanistically, DPEP2 impeded epithelial-mesenchymal transition (EMT) via the MAP3K7-mediated NF-κB signaling. Immunological analysis suggested that low level of DPEP2 and high level of M1 macrophages led to poor prognosis, whereas patients with high level of DPEP2 and low level of M2 had the best survival. Subsequently, a co-culture system was established to verify the effect of DPEP2 on M2 macrophages. The results showed that DPEP2 inhibited M2 macrophages polarization in a NF-κB-dependent manner. In addition, we found that DPEP2 antagonized the tumor-promoting effects of M2 macrophages by depleting LTD4. In vivo experiments indicated that high DPEP2 levels resulted in fewer lung metastases and less M2 macrophage infiltration. Overall, our studies suggest that DPEP2 might be a promising therapeutic target for highly metastatic p53-loss NSCLC by inhibiting tumor metastasis and M2 macrophage capacity.