title: Cigarette smoke extracts induce overexpression of the proto-oncogenic gene interleukin-13 receptor α2 through activation of the PKA-CREB signaling pathway to trigger malignant transformation of lung vascular endothelial cells and angiogenesis.
abstract: Cigarette smoking is a major cause of lung cancer. Tumor-associated endothelial cells (TAECs) play important roles in tumor angiogenesis and metastasis. However, whether cigarette smoking can trigger genesis of lung TAECs has not been reported yet. In the current study, we used lung endothelial cell (EC) lines as a model to study the pathological effect of cigarette smoke extracts (CSEs) on human lung ECs, and found that a lower dose of 4% CSEs obviously caused abnormal morphological changes in ECs, increased the permeability of endothelial monolayer, while a higher concentration of 8% CSEs caused EC apoptosis. Strikingly, CSEs induced a 117-fold overexpression of a pro-tumorigenic interleukin-13 receptor α2 gene (IL-13Rα2, also named as CT-19) through activation of the protein kinase A (PKA) and cAMP response element-binding protein (CREB) signaling pathway. A PKA specific inhibitor H89 completely abolished CSEs-induced IL-13Rα2 overexpression. The overexpression of IL-13Rα2 in lung ECs significantly increased the tumorigenic, migratory, and angiogenic capabilities of the cells, suggesting that IL-13Rα2 promotes genesis of lung TAECs. Together, our data show that CSEs activate the PKA, CREB, and IL-13Rα2 axis in lung ECs, and IL-13Rα2 promotes the malignant transformation of lung ECs and genesis of TAECs with robust angiogenic and oncogenic capabilities. Our study provides new insight into the mechanism of CSEs-triggered lung cancer angiogenesis and tumorigenesis, suggesting that the PKA-CREB-IL-13Rα2 axis is a potential target for novel anti-lung tumor angiogenesis and anti-lung cancer drug discovery.
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Meng
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Huaidong
authors.initials: H
authors.lastname: Liao
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Wenming
authors.initials: W
authors.lastname: Liu
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Zihe
authors.initials: Z
authors.lastname: Huo
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Zhifei
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: zhouqs@suda.edu.cn.
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D017209:Apoptosis; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D002463:Cell Membrane Permeability; D002465:Cell Movement; D048430:Cell Shape; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D000073865:Cigarette Smoking / Q000009:adverse effects*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000473:pathology*; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000473:pathology*; D015398:Signal Transduction
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D053663:Interleukin-13 Receptor alpha2 Subunit; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Angiogenesis; CT-19; Cigarette smoke extract; IL-13Rα2; Lung cancer; Tumor-associated endothelial cells