Chaojie Li1, Nannan Yang1, Zhijin Chen1, Ning Xia1, Qungang Shan1, Ziyin Wang1, Jian Lu1, Mingyi Shang2, Zhongmin Wang3,4. 1. Department of Radiology, Ruijin Hospital Luwan Branch, Shanghai Jiao Tong University School of Medicine, No. 149 Chongqing South Road, Shanghai, 200025, China. 2. Department of Interventional Radiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xianxia Road, Shanghai, 200336, China. myshang1969@aliyun.com. 3. Department of Radiology, Ruijin Hospital Luwan Branch, Shanghai Jiao Tong University School of Medicine, No. 149 Chongqing South Road, Shanghai, 200025, China. wzm11896@rjh.com.cn. 4. Department of Interventional Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200000, China. wzm11896@rjh.com.cn.
Abstract
BACKGROUND: Drug resistance and metastasis involving hypoxic tumor environments and persistent stem cell populations are detrimental to the survival of patients with non-small cell lung carcinoma (NSCLC). Tie1 is upregulated in hypoxia and is believed to counteract the effectiveness of platinum agents by promoting the stemness properties in cells. We have investigated the association of Tie1 with HIF-1α and cisplatin resistance in NSCLC cell lines. METHODS: The expression of Tie1 in a pulmonary microvascular endothelial cell line (HPMEC) and NSCLC cell lines was detected using qRT-PCR and western blotting. The effect of Tie1 on cell stemness and migration was examined by sphere-forming and transwell assays in NSCLC cells with Tie1 silenced. The regulation of Tie1 by HIF-1α was evaluated by a dual-luciferase reporter assay and chromatin immunoprecipitation. RESULTS: We found that hypoxia could induce stemness and cisplatin resistance in vitro. Tie1 was expressed at low levels in NSCLC cells when compared with human pulmonary microvascular endothelial cells, however, its expression was increased by hypoxia. Additionally, Tie1 knockdown could reduce stemness properties and increase sensitivity to cisplatin in vitro and in a xenograft mouse model. The promoter of Tie1 contains two predicted hypoxia-response elements (HREs). We mutated both HRE sites and conducted chromatin immune-precipitation and promoter luciferase reporter assays and were able to conclude that the induction of Tie1 by hypoxia was HIF-1α-dependent. CONCLUSIONS: Our findings indicated that Tie1 is upregulated in a hypoxic environment by HIF-1α and contributes to tumorigenesis and cisplatin resistance through the promotion of stemness in NSCLC cells.
BACKGROUND: Drug resistance and metastasis involving hypoxic tumor environments and persistent stem cell populations are detrimental to the survival of patients with non-small cell lung carcinoma (NSCLC). Tie1 is upregulated in hypoxia and is believed to counteract the effectiveness of platinum agents by promoting the stemness properties in cells. We have investigated the association of Tie1 with HIF-1α and cisplatin resistance in NSCLC cell lines. METHODS: The expression of Tie1 in a pulmonary microvascular endothelial cell line (HPMEC) and NSCLC cell lines was detected using qRT-PCR and western blotting. The effect of Tie1 on cell stemness and migration was examined by sphere-forming and transwell assays in NSCLC cells with Tie1 silenced. The regulation of Tie1 by HIF-1α was evaluated by a dual-luciferase reporter assay and chromatin immunoprecipitation. RESULTS: We found that hypoxia could induce stemness and cisplatin resistance in vitro. Tie1 was expressed at low levels in NSCLC cells when compared with human pulmonary microvascular endothelial cells, however, its expression was increased by hypoxia. Additionally, Tie1 knockdown could reduce stemness properties and increase sensitivity to cisplatin in vitro and in a xenograft mouse model. The promoter of Tie1 contains two predicted hypoxia-response elements (HREs). We mutated both HRE sites and conducted chromatin immune-precipitation and promoter luciferase reporter assays and were able to conclude that the induction of Tie1 by hypoxia was HIF-1α-dependent. CONCLUSIONS: Our findings indicated that Tie1 is upregulated in a hypoxic environment by HIF-1α and contributes to tumorigenesis and cisplatin resistance through the promotion of stemness in NSCLC cells.
Authors: William D Travis; Elisabeth Brambilla; Andrew G Nicholson; Yasushi Yatabe; John H M Austin; Mary Beth Beasley; Lucian R Chirieac; Sanja Dacic; Edwina Duhig; Douglas B Flieder; Kim Geisinger; Fred R Hirsch; Yuichi Ishikawa; Keith M Kerr; Masayuki Noguchi; Giuseppe Pelosi; Charles A Powell; Ming Sound Tsao; Ignacio Wistuba Journal: J Thorac Oncol Date: 2015-09 Impact factor: 15.609
Authors: Ting-Yuan David Cheng; Susanna M Cramb; Peter D Baade; Danny R Youlden; Chukwumere Nwogu; Mary E Reid Journal: J Thorac Oncol Date: 2016-06-27 Impact factor: 15.609