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Induces Systemic Inflammation and Adenocarcinoma in the Lung1
* Center for Immunobiology and
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202; and
Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229
To study the functional role of apoptosis inhibition of myeloid lineage cells in tumor formation, apoptosis inhibitor 6 (Api6/AIM/Sp
) was overexpressed in a myeloid-specific c-fms-rtTA/(TetO)7-CMV-Api6 bitransgenic mouse model under the control of the c-fms promoter/intron 2. In this bitransgenic system, the Api6-Flag fusion protein was expressed in myeloid lineage cells after doxycycline treatment. Induction of Api6 abnormally elevated levels of macrophages, neutrophils, and dendritic cells in the bone marrow, blood, and lung in vivo. BrdU incorporation and annexin V binding studies showed systemically increased cell proliferation and inhibition of apoptosis in myeloid lineage cells. Api6 overexpression activated oncogenic signaling pathways, including Stat3, Erk1/2, and p38 in myeloid lineage cells in multiple organs of the bitransgenic mice. In the lung, severe inflammation and massive tissue remodeling were observed in association with increased expression of procancer cytokines/chemokines, decreased expression of proapoptosis molecule genes, and increased expression of matrix metalloproteinase genes as a result of Api6 overexpression. Oncogenic CD11b+/Gr-1+ myeloid-derived suppressor cells were systemically increased. After Api6 overexpression, lung adenocarcinoma was observed in bitransgenic mice with a 35% incidence rate. These studies suggest that dysregulation of myeloid cell populations by extracellular Api6 signaling leads to abnormal myelopoiesis and lung cancer.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by National Institutes of Health Grants HL087001 (to H.D.), HL-061803 (to C.Y. and H.D.), and HL-067862 (to C.Y. and H.D.) and by an Indiana University Cancer Center Translational Research Acceleration Collaboration (ITRAC) Award (to C.Y.).
2 Address correspondence and reprint requests to Dr. Cong Yan, Center for Immunobiology, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202. E-mail address: coyan{at}iupui.edu or Dr. Hong Du, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229. E-mail address: hong.du{at}cchmc.org
3 Abbreviations used in this paper: DC, dendritic cell; Api6, apoptosis inhibitory 6; LAL, lysosomal acid lipase; m, murine (prefix); MDSC, myeloid-derived suppressor cell; MMP, matrix metalloproteinase; PI, propidium iodide; rtTA, reverse tetracycline-responsive transactivator; SP-C, surfactant protein C; TetO, tetracycline operator; WT, wild type.
4 The online version of this article contains supplemental material.
This article has been cited by other articles:
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  P. Qu, H. Du, X. Wang, and C. Yan Matrix Metalloproteinase 12 Overexpression in Lung Epithelial Cells Plays a Key Role in Emphysema to Lung Bronchioalveolar Adenocarcinoma Transition Cancer Res., September 15, 2009; 69(18): 7252 - 7261. [Abstract] [Full Text] [PDF]
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