Myeloid-specific expression of Api6/AIM/Sp alpha induces systemic inflammation and adenocarcinoma in the lung.
Myeloid-specific expression of Api6/AIM/Sp alpha induces systemic inflammation and adenocarcinoma in the lung.
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DOI：
10.4049/jimmunol.182.3.1648
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发表时间：
2009-02-01
期刊：
影响因子：
--
通讯作者：
Yan C
中科院分区：
文献类型：
--
作者：
Qu P;Du H;Li Y;Yan C
为了研究髓系细胞凋亡抑制在肿瘤形成中的作用，在c-fms启动子/内含子2调控下，在髓系特异性c-fms-rtTA/(Teto)7-α-API6双转基因小鼠模型中过表达了凋亡抑制因子6(Api6/Aim/Sp FLAG)。Api6在体内诱导骨髓、血液和肺中巨噬细胞、中性粒细胞和树突状细胞水平异常升高。BrdU掺入和Annexin V结合研究显示，系统性地促进了髓系细胞的增殖和抑制了细胞的凋亡。Api6的过表达激活了双转基因小鼠多器官髓系细胞中的STAT3、ERK1/2和p38等致癌信号通路。在肺组织中，由于Api6的过度表达，致癌细胞因子/趋化因子表达增加，促凋亡分子基因表达降低，基质金属蛋白酶基因表达增加，出现严重的炎症和大量的组织重塑。致癌性CD11b+/Gr-1+髓系抑制细胞(MDSCs)明显增多。在Api6过表达后，双转基因小鼠出现肺腺癌，发生率为35%。这些研究表明，细胞外Api6信号对髓系细胞群体的失调会导致异常的骨髓生成和肺癌。
In order 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, 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 pro-cancer cytokines/chemokines, decreased-expression of pro-apoptosis molecule genes and increased-expression of matrix metalloproteinase genes as a result of Api6 overexpression. Oncogenic CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSCs) 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.
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