This competitive renewal application will continue examining the molecular mechanisms by which nickel compounds mediate lung carcinogenesis. In particular, this proposal seeks to identify the molecular mechanisms linking nickel-induced lung sustained inflammation to tumorigenicity of human bronchial epithelial cells (HBECs) in vitro and in vivo. Although there is an association between nickel- induced sustained airway inflammation and lung cancer development, the molecular mechanisms linking nickel exposure to the sustained lung chronic inflammation are not understood yet. The studies obtained from the last funding period and preliminary studies demonstrate that nickel exposure results in the activation of the nuclear factor-:B (NF:B), which in turn mediates COX-2 induction. Our studies also show that nickel exposure enables activation of AP-1, which in turn mediates TNF-1 induction. Furthermore, we find that TNF-1 enables COX-2 induction through the NFAT-dependent pathway. In addition, we find that there is crosstalk between the NFAT and NF?B pathways during cellular response to nickel exposure. Thus, the main hypothesis of this renewal proposal is that the NFAT/ NF?B activation and the pro-inflammatory TNF-1 and COX-2 induction will form positive inflammatory feedback loops, which are responsible for the formation and maintenance of sustained chronic lung inflammation and the induction of lung epithelial cell tumorigenicity due to nickel exposure. We propose the following Specific Aims: 1), To test the hypothesis that the inflammatory positive feedback loops being formed by NF?B, NFAT, and TNF1 are responsible for the maintenance of sustained COX-2 induction due to nickel exposure in HBECs;2), To determine the role of the positive inflammatory feedback loops in the development of tumorigenicity induced by nickel exposure in HBECs.;3), To assess the central role of TNF-1 in nickel-induced chronic lung inflammation and its mechanisms in vivo. The overall goal of this proposal is to clarify the formation of positive inflammatory feedback loops among NFAT, NF?B, TNF-1 and COX-2, in nickel exposure both in vitro and in vivo, and to determine the role of the positive inflammatory feedback loops in nickel-induced HBECs'tumorigenicity, as well as the central role of TNF-1 in the maintenance of lung sustained chronic inflammation and lung carcinogenesis during nickel exposure in vivo. Success of the proposal will facilitate our understanding of the molecular mechanism(s) that lead to the formation and maintenance of a lung chronic inflammatory microenvironment, and its role in lung carcinogenesis due to nickel exposure. A better understanding of these issues may provide valuable information for the designing of more effective agents for the prevention and therapy of lung cancers. We believe that the proposed contribution of positive inflammatory feedback loop responsible for nickel-induced lung tumorigenicity is novel.
The elucidation of the molecular mechanisms that are involved in the maintenance of the sustained lung chronic inflammatory microenvironment, a process with well-documented links to lung cancer development, will be of great significance in facilitating our understanding of lung cancer development and will provide valuable information that is urgently needed for designing more effective agents for prevention and therapy of lung cancers. The goal of this application is to test the hypothesis that there are certain positive feedback loop(s) among pro- inflammatory TNF-1 and COX-2 induction and NFAT/NF:B activation, which are responsible for the sustained activation of NFAT/ NF?B pathway leading to constitutive COX-2 overexpression, subsequently resulting in lung cancer development from chronic lung inflammation caused by nickel exposure. The overall goal of this proposal is to clarify the relationship among the activation of NFAT, NF?B and induction of TNF-1 and COX-2, in nickel-caused lung inflammatory environment, and to understand the molecular mechanisms implicated in the mediation of this inflammatory environment in lung cancer development both in vitro and in vivo.
|Huang, Haishan; Jin, Honglei; Zhao, Huirong et al. (2017) RhoGDI? promotes Sp1/MMP-2 expression and bladder cancer invasion through perturbing miR-200c-targeted JNK2 protein translation. Mol Oncol 11:1579-1594|
|Zhou, C; Huang, C; Wang, J et al. (2017) LncRNA MEG3 downregulation mediated by DNMT3b contributes to nickel malignant transformation of human bronchial epithelial cells via modulating PHLPP1 transcription and HIF-1? translation. Oncogene 36:3878-3889|
|Yu, Yonghui; Jin, Honglei; Xu, Jiheng et al. (2017) XIAP overexpression promotes bladder cancer invasion in vitro and lung metastasis in vivo via enhancing nucleolin-mediated Rho-GDI? mRNA stability. Int J Cancer :|
|Huang, Chao; Zeng, Xingruo; Jiang, Guosong et al. (2017) XIAP BIR domain suppresses miR-200a expression and subsequently promotes EGFR protein translation and anchorage-independent growth of bladder cancer cell. J Hematol Oncol 10:6|
|Jin, Honglei; Xie, Qipeng; Guo, Xirui et al. (2017) p63? protein up-regulates heat shock protein 70 expression via E2F1 transcription factor 1, promoting Wasf3/Wave3/MMP9 signaling and bladder cancer invasion. J Biol Chem 292:15952-15963|
|Jiang, Guosong; Huang, Chao; Li, Jingxia et al. (2017) Role of STAT3 and FOXO1 in the Divergent Therapeutic Responses of Non-metastatic and Metastatic Bladder Cancer Cells to miR-145. Mol Cancer Ther 16:924-935|
|Zhu, Junlan; Li, Yang; Tian, Zhongxian et al. (2017) ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 Axis. Mol Ther Nucleic Acids 7:299-313|
|Jin, Honglei; Xu, Jiheng; Guo, Xirui et al. (2016) XIAP RING domain mediates miR-4295 expression and subsequently inhibiting p63? protein translation and promoting transformation of bladder epithelial cells. Oncotarget 7:56540-56557|
|Xu, Zhou; Zeng, Xingruo; Xu, Jiawei et al. (2016) Isorhapontigenin suppresses growth of patient-derived glioblastoma spheres through regulating miR-145/SOX2/cyclin D1 axis. Neuro Oncol 18:830-9|
|Wang, Y; Xu, J; Gao, G et al. (2016) Tumor-suppressor NF?B2 p100 interacts with ERK2 and stabilizes PTEN mRNA via inhibition of miR-494. Oncogene 35:4080-90|
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