Myeloid-specific expression of Api6/AIM/Spα induces systemic inflammation and adenocarcinoma in the lung

Peng Qu, Hong Du, Yuan Li, Cong Yan

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

To study the functional role of apoptosis inhibition of myeloid lineage cells in tumor formation, apoptosis inhibitor 6 (Api6/AIM/Spα) 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.

Original languageEnglish
Pages (from-to)1648-1659
Number of pages12
JournalJournal of Immunology
Volume182
Issue number3
StatePublished - Feb 1 2009

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Myeloid Cells
Inflammation
Apoptosis
Myelopoiesis
Lung
Doxycycline
Annexin A5
Bromodeoxyuridine
Matrix Metalloproteinases
Chemokines
Dendritic Cells
Introns
Lung Neoplasms
Neutrophils
Bone Marrow
Macrophages
Cell Proliferation
Adenocarcinoma of lung
Cytokines
Gene Expression

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Myeloid-specific expression of Api6/AIM/Spα induces systemic inflammation and adenocarcinoma in the lung. / Qu, Peng; Du, Hong; Li, Yuan; Yan, Cong.

In: Journal of Immunology, Vol. 182, No. 3, 01.02.2009, p. 1648-1659.

Research output: Contribution to journalArticle

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