Circulating AIM Prevents Hepatocellular Carcinoma through Complement Activation

• AIM is incorporated into normal hepatocytes and suppresses lipid storage
• AIM accumulates on the HCC cell surface and activates complement cascade
• Cell-surface AIM-induced complement activation provokes HCC cell necrosis
• AIM prevents steatosis-associated HCC tumor development

SummaryHepatocellular carcinoma (HCC) is a widespread fatal disease and the third most common cause of cancer deaths. Here, we show the potent anti-HCC effect of the circulating protein AIM. As in adipocytes, AIM is incorporated into normal hepatocytes, where it interferes with lipid storage. In contrast, AIM accumulates on the HCC cell surface and activates the complement cascade via inactivating multiple regulators of complement activation. This response provokes necrotic cell death specifically in AIM-bound HCC cells. Accordingly, AIM−/− mice were highly susceptible to steatosis-associated HCC development, whereas no AIM+/+ mouse developed the disease despite comparable liver inflammation and fibrosis in response to a long-term high-fat diet. Administration of AIM prevented tumor development in AIM−/− mice, and HCC induction by diethylnitrosamine was more prominent in AIM−/− than wild-type mice. These findings could be the basis for novel AIM-based therapeutic strategies for HCC.

Graphical AbstractFigure optionsDownload as PowerPoint slide