Targeting hepatocyte MagL regulates the progression of colorectal liver metastases during liver ischemia-reperfusion

Abstract Background Colorectal cancer (CRC) commonly metastasizes. The liver is the most frequent site of metastases and dominates the length of survival for this disease. In such cases, surgical resection is usually the first choice of treatment, but postoperative recurrence is very common. To control hemorrhage, liver ischemia-reperfusion (LIR) becomes a common event during hepatic surgery. Many studies show that LIR is one of the most important causes of CRC recurrence after hepatectomy. Monoacylglycerol lipase (MagL) is an enzyme playing an important role in liver metabolism, and it has also been found multiple effects in several hepatic disease models. Methods We silenced the expression of MagL in hepatocytes through in vivo transfection reagents. We injected colorectal cancer cells, MC38, into the spleen and then clamped the vascular structures in the left hepatic lobe for 90 minutes to construct an LIR model in the context of colorectal liver metastases. We used a transwell co-culture system to investigate the effect of hepatocyte MagL on the polarization of macrophages and its secondary effect on colon cancer cells in vitro. Results We found that LIR significantly promoted MC38 tumor growth in the liver, and targeting hepatocyte MagL reversed this tumor-promoting trend. Further studies revealed that targeting hepatocyte MagL significantly inhibited the M2 polarization of monocyte-derived macrophages (MoMFs) induced by its secondary lipid metabolite prostaglandin E2 (PGE2) after LIR, and liver fibrosis induced by macrophages with reparative phenotypes was simultaneously alleviated. All of these events caused reduced colon cancer cell migration and invasion. Conclusion Targeting hepatocyte MagL could disrupt the immune and fibrotic microenvironment which can promote tumor growth, by affecting the phenotypic switch of immune cells to immunosuppression after LIR, thereby alleviating the recurrence of colorectal liver metastases caused by LIR.