Circulating AIM Prevents Hepatocellular Carcinoma through Complement Activation
Natsumi Maehara,
Satoko Arai,
Mayumi Mori,
Yoshihiro Iwamura,
Jun Kurokawa,
Toshihiro Kai,
Shunsuke Kusunoki,
Kaori Taniguchi,
Kazutaka Ikeda,
Osamu Ohara,
Ken-ichi Yamamura,
Toru Miyazaki
Affiliations
Natsumi Maehara
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Satoko Arai
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Mayumi Mori
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Yoshihiro Iwamura
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Jun Kurokawa
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Toshihiro Kai
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Shunsuke Kusunoki
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Kaori Taniguchi
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Kazutaka Ikeda
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
Osamu Ohara
Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan
Ken-ichi Yamamura
Center for Animal Resources and Development, Kumamoto University, Kumamoto 860-0811, Japan
Toru Miyazaki
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; CREST, Japan Science and Technology Agency, Tokyo 113-0033, Japan; Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo 113-0033, Japan; Corresponding author
Summary: 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. : Nonalcoholic fatty liver disease is a manifestation of metabolic syndrome and is a potent risk factor for the development of hepatocellular carcinoma (HCC). Maehara et al. now show that circulating AIM protein is incorporated into normal hepatocytes, where it interferes with lipid storage. In HCC cells, AIM accumulates on the cell surface and specifically provokes cell death. AIM has a potent preventive effect on both fatty liver and HCC, which could form the basis for therapeutic strategies for this widespread and fatal disease.
