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.

Public Health Relevance

The proposed research will study the involvement of Twist1 in lung carcinogenesis and its mechanisms and the clinical importance of Twist1. The findings of this research could provide means to better understand molecular mechanisms of lung cancer development after different carcinogen exposure, and identify novel molecular targets for lung cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15ES026789-01
Application #
9098413
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (82))
Program Officer
Tyson, Frederick L
Project Start
2016-09-01
Project End
2019-08-31
Budget Start
2016-09-01
Budget End
2019-08-31
Support Year
1
Fiscal Year
2016
Total Cost
$435,232
Indirect Cost
$135,232
Name
Texas Tech University
Department
Type
Organized Research Units
DUNS #
041367053
City
Lubbock
State
TX
Country
United States
Zip Code
79409
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