Circulating AIM Prevents Hepatocellular Carcinoma through Complement Activation

Abstract

Hepatocellular 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.

Dietary fructose‐induced hepatocellular carcinoma development manifested in mice lacking apoptosis inhibitor of macrophage (AIM)

“…From these results, it is likely that carcinogenesis was induced in hepatocytes at a considerably high rate only by the HFrD. This fact became apparent because we used AIM -/-mice, in which cancerous hepatocytes are not eliminated and keep growing (Maehara et al 2014).…”

“…No wild-type mice showed such multiple HCC tumors after the same HFrD challenge ( Fig. 2A,B), similar to those fed the HFD (Maehara et al 2014), consistent with the findings of previous reports by other groups who showed that HCC is rarely induced in wild-type mice by HFrD or HFD challenge alone (Hill-Baskin et al 2009;Kumamoto et al 2013;Yoshimoto et al 2013). RNA sequencing analysis of the liver from AIM -/-mice fed the HFrD at 0, 12 and 52 weeks showed changes in the expression of genes for cancer-related canonical pathways in parallel with HCC development (Fig.…”

“…No AIM -/-mice fed the HFrD showed HCC macroscopically or histologically at 12 or 40 weeks ( Fig. 2A,B), whereas in AIM -/-mice fed the HFD, HCC incidence was 10% and 75%, respectively, in macroscopic analysis (Maehara et al 2014). No wild-type mice showed such multiple HCC tumors after the same HFrD challenge ( Fig.…”

“…Interestingly, AIM accumulates on the surface of cancerous hepatocytes, and surfacebound AIM specifically stimulates cancer cell death by necrosis through activation of the complement cascade (Maehara et al 2014;Miyazaki & Arai 2015). In contrast to wild-type mice, in which HCC tumors seldom develop after HFD-induced severe steatosis, all AIM -/-mice bear multiple tumors when fed an HFD for 1 year (Maehara et al 2014). This finding is consistent with the fact that only a small proportion of human individuals show an extremely low level of serum AIM (e.g., <1.0 lg/mL; Yamazaki et al 2014), and thus, the incidence of HCC based on steatosis/NASH in humans is low (<10%) (Hytiroglou et al 2007;Park et al 2010;He & Karin 2011).…”

“…AIM associates with IgM pentamers in blood, which protect AIM from renal excretion and thus maintain a high level of circulating AIM (2.5--10 lg/mL) (Arai et al 2013). Interestingly, AIM accumulates on the surface of cancerous hepatocytes, and surfacebound AIM specifically stimulates cancer cell death by necrosis through activation of the complement cascade (Maehara et al 2014;Miyazaki & Arai 2015). In contrast to wild-type mice, in which HCC tumors seldom develop after HFD-induced severe steatosis, all AIM -/-mice bear multiple tumors when fed an HFD for 1 year (Maehara et al 2014).…”