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Api6/AIM/Sp?/CD5L overexpression in alveolar type II epithelial cells induces spontaneous lung adenocarcinoma.

ABSTRACT: Chronic inflammation is an important contributor to the development of lung cancers, one of the most common malignancies worldwide, but the underlying molecular mechanisms of inflammation that specifically cue cancer risk remain poorly understood. Apoptosis inhibitor 6 (Api6, also known as AIM, Sp-?, and CD5L) is a downstream target gene of neutral lipids and peroxisome proliferator-activated receptor gamma in lung alveolar type II (AT II) epithelial cells. An association among increased expression of Api6 in certain settings of pathogenic lung inflammation in mice prompted us to hypothesize a possible role in cancer. Here, we report that Api6 promotes malignant transformation by limiting lung epithelial cell apoptosis and promoting immune escape. The specific function of Api6 in AT II cells was determined by using a doxycycline-inducible Api6 mouse model. Api6 overexpression inhibited apoptosis and activated oncogenic signaling in AT II lung epithelial cells, inducing emphysema and adenocarcinoma. In addition, Api6 overexpression in AT II cells increased the concentrations of proinflammatory cytokines/chemokines in bronchoalveolar lavage fluid and serum, promoting expansion of myeloid-derived suppressor cells (MDSC) in lung and blood but not in bone marrow or spleen. Lung MDSCs suppressed T-cell proliferation and activity in vitro and reduced levels of T cells in vivo following doxycycline treatment to activate Api6. Together, our findings establish that Api6 promotes lung tumorigenesis by blocking a mechanism of epithelial apoptosis that would normally support immunosurveillance.

SUBMITTER: Li Y

PROVIDER: S-EPMC3156382 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Api6/AIM/Spα/CD5L overexpression in alveolar type II epithelial cells induces spontaneous lung adenocarcinoma.

Li Yuan Y Qu Peng P Wu Lingyan L Li Beilin B Du Hong H Yan Cong C

Cancer research 20110622 16

Chronic inflammation is an important contributor to the development of lung cancers, one of the most common malignancies worldwide, but the underlying molecular mechanisms of inflammation that specifically cue cancer risk remain poorly understood. Apoptosis inhibitor 6 (Api6, also known as AIM, Sp-α, and CD5L) is a downstream target gene of neutral lipids and peroxisome proliferator-activated receptor gamma in lung alveolar type II (AT II) epithelial cells. An association among increased express ...[more]

PMID: 21697282

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Project description:BackgroundAlveolar macrophages (AMs) and AM-produced matrix metalloprotease (MMP)-12 are known to play critical roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). The apoptosis inhibitor of the macrophages (AIM)/CD5 molecule-like (CD5L) is a multifunctional protein secreted by the macrophages that mainly exists in the blood in a combined form with the immunoglobulin (Ig)M pentamer. Although AIM has both facilitative and suppressive roles in various diseases, its role in COPD remains unclear.MethodsWe investigated the role of AIM in COPD pathogenesis using porcine pancreas elastase (PPE)-induced and cigarette smoke-induced emphysema mouse models and an in vitro model using AMs. We also analyzed the differences in the blood AIM/IgM ratio among nonsmokers, healthy smokers, and patients with COPD and investigated the association between the blood AIM/IgM ratio and COPD exacerbations and mortality in patients with COPD.ResultsEmphysema formation, inflammation, and cell death in the lungs were attenuated in AIM-/- mice compared with wild-type (WT) mice in both PPE- and cigarette smoke-induced emphysema models. The PPE-induced increase in MMP-12 was attenuated in AIM-/- mice at both the mRNA and protein levels. According to in vitro experiments using AMs stimulated with cigarette smoke extract, the MMP-12 level was decreased in AIM-/- mice compared with WT mice. This decrease was reversed by the addition of recombinant AIM. Furthermore, an analysis of clinical samples showed that patients with COPD had a higher blood AIM/IgM ratio than healthy smokers. Additionally, the blood AIM/IgM ratio was positively associated with disease severity in patients with COPD. A higher AIM/IgM ratio was also associated with a shorter time to the first COPD exacerbation and higher all-cause and respiratory mortality.ConclusionsAIM facilitates the development of COPD by upregulating MMP-12. Additionally, a higher blood AIM/IgM ratio was associated with poor prognosis in patients with COPD.Trial registrationThis clinical study, which included nonsmokers, healthy smokers, and smokers with COPD, was approved by the Ethics Committee of the Hokkaido University Hospital (012-0075, date of registration: September 5, 2012). The Hokkaido COPD cohort study was approved by the Ethics Committee of the Hokkaido University School of Medicine (med02-001, date of registration: December 25, 2002).

Dataset Information

Api6/AIM/Sp?/CD5L overexpression in alveolar type II epithelial cells induces spontaneous lung adenocarcinoma.

Publications

Api6/AIM/Spα/CD5L overexpression in alveolar type II epithelial cells induces spontaneous lung adenocarcinoma.

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