PIPKIγ Regulates CCL2 Expression in Colorectal Cancer by Activating AKT-STAT3 Signaling

Abstract

Colorectal cancer (CRC) remains the third most commonly diagnosed cancer, ranking second among the most common causes of cancer-related mortality. Immune checkpoint therapy has recently been shown to have great potential. However, only some patients respond to immune checkpoint blockade, indicating the unmet need for determining the underlying mechanism of colorectal cancer immunosuppression. In this study, we analyzed The Cancer Genome Atlas (TCGA) datasets and found that high expression of PIPKIγ positively correlated with tumor-associated macrophage infiltration. Further loss-of-function studies revealed that silencing PIPKIγ greatly reduced CCL2 expression at both the mRNA and protein levels, leading to weak chemotaxis of cancer cells to macrophages. Mechanistically, PIPKIγ facilitated PI3K-Akt-mTOR signaling pathway activation to increase STAT3 phosphorylation levels, thus triggering CCL2 transcription to enhance tumor-associated macrophage recruitment. These findings identify the PIPKIγ signaling pathway as a new actor in colorectal cancer immunosuppression and a potential therapeutic target for this common cancer.