title: 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.
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Maehara
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Arai
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Mori
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Iwamura
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kurokawa
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kai
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kusunoki
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.affiliation: Center for Animal Resources and Development, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Yamamura
authors.affiliation: 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. Electronic address: tm@m.u-tokyo.ac.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Miyazaki
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000097:blood / Q000276:immunology* / Q000494:pharmacology; D003167:Complement Activation / Q000276:immunology*; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000097:blood / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000276:immunology; D011971:Receptors, Immunologic / Q000097:blood / Q000276:immunology*; D051116:Receptors, Scavenger; D012307:Risk Factors
chemical_list: D051017:Apoptosis Regulatory Proteins; C117272:Cd5l protein, mouse; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger