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Your Environment. Your Health.

CARCINOGEN-SPECIFIC TWIST1 REGULATION IN LUNG EPITHELIAL CELLS

Export to Word (http://www.niehs.nih.gov//portfolio/index.cfm/portfolio/grantdetail/grant_number/R15ES026789/format/word)
Principal Investigator: Gao, Weimin
Institute Receiving Award West Virginia University
Location Morgantown, WV
Grant Number R15ES026789
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Sep 2016 to 31 Mar 2021
DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Twist1, a transcriptional factor with upregulated expression in various cancers, plays important roles in cancer development and metastasis. However, the exact mechanistic pathways by which Twist1 regulates carcinogen-specific lung cancer initiation and progression remain largely unknown. Therefore, new insight into how lung cancer initiates and progresses mediated by Twist1 is urgently needed. Our preliminary data suggest that overexpression of Twist1 is frequently found in lung cancer and correlated to its prognosis, Twist1 overexpression could be carcinogen-specific and related to its underlying molecular changes, and inhibition of Twist1 could lead to the decrease of tumorigenicity of lung cancer cells. In the current application, we propose to do the followings: 1) Evaluate the role of Twist1 in carcinogen-specific lung carcinogenesis using in vitro and in vivo models. (a) Evaluate the involvement of Twist1 in cellular response to BaP or NNK in lung epithelial cells and (b) Assess the importance of Twist1 alterations in the tumor development in BaP or NNK-induced lung cancer mouse model. 2) Identify the Twist1-mediated molecular mechanisms in carcinogen-specific lung tumorigenesis. (a) Evaluate the regulation of Twist1 cellular localization by shuttling factors (G3BP2, p62, and exportins) and Twist1-interacting proteins after BaP or NNK exposure and (b) Determine Twist1-mediated signaling molecules including p53, K-ras, and EGFR after BaP or NNK exposure. 3) Investigate the clinical significance of targeting Twist1 for lung cancer treatment. (a) Evaluate the combinative effect of Twist1 and the EGFR TKI in cell lines and the xenograft mouse model and (b) Examine the anti-drug resistance of targeting Twist1 for the EGFR TKI in cell lines and the xenograft mouse model. These studies will help improve our understanding of carcinogen-specific molecular progression of lung carcinogenesis mediated by Twist1, and identify the clinical significance of targeting Twist1 for lung cancer treatment.
Science Code(s)/Area of Science(s) Primary: 03 - Carcinogenesis/Cell Transformation
Publications See publications associated with this Grant.
Program Officer Frederick Tyson
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