Lung cancer is the leading cause of cancer-related death in the United States. Cigarette smoke (CS) is a well- known risk for lung cancer. Inflammation has clearly emerged as a key process contributing to the development of lung and other cancers. However, the gene targets and pathways modulated by inflammation that impact cancer development have not been clearly elucidated. This application builds on emerging studies from the literature and by our group that implicate an important role for MUC1 in linking inflammation and carcinogenesis. The central hypothesis of this application is that airway inflammation resulting from CS induces MUC1 expression, which triggers lung cancer development through potentiation of the EGFR- mediated Akt and extracellular signal-regulated kinases (ERK) pathways. This hypothesis will be tested in the three Specific Aims: 1. To determine if the pro-inflammatory cytokine TNF? mediates CS-induced MUC1 expression in bronchial epithelial cells and if MUC1 potentiates cell transformation;2. To determine if MUC1 facilitates CS-induced bronchial epithelial cell transformation through potentiation of the EGFR-mediated Akt and ERK pathways;3. To investigate the role of MUC1 in CS-induced lung carcinogenesis with CS-derived carcinogen benzo(a)pyrene (BaP)- and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced A/J lung cancer models and in a xenografted human lung tumor model in nude mice. Successful completion of this study will likely reveal a new molecular mechanism of CS-induced lung carcinogenesis that involves Muc1 and will provide new insights into how inflammation influences cell transformation and tumor development and could identify novel targets for prevention and intervention therapy for lung cancer.

Public Health Relevance

The proposed research will likely unravel a new molecular mechanism of tobacco smoke-induced lung carcinogenesis. The outcome from this study may lead to new strategies for lung cancer prevention and therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES017328-03
Application #
8240086
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Reinlib, Leslie J
Project Start
2010-08-09
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$427,112
Indirect Cost
$205,729
Name
Lovelace Biomedical & Environmental Research
Department
Type
DUNS #
045911138
City
Albuquerque
State
NM
Country
United States
Zip Code
87108
Wang, Qiong; Chen, Wenshu; Bai, Lang et al. (2014) Receptor-interacting protein 1 increases chemoresistance by maintaining inhibitor of apoptosis protein levels and reducing reactive oxygen species through a microRNA-146a-mediated catalase pathway. J Biol Chem 289:5654-63
Xu, Xiuling; Wells, Alexandria; Padilla, Mabel T et al. (2014) A signaling pathway consisting of miR-551b, catalase and MUC1 contributes to acquired apoptosis resistance and chemoresistance. Carcinogenesis 35:2457-66
Xu, Xiuling; Padilla, Mabel T; Li, Bilan et al. (2014) MUC1 in macrophage: contributions to cigarette smoke-induced lung cancer. Cancer Res 74:460-70
Wang, Qiong; Shi, Shaoqing; He, Weiyang et al. (2014) Retaining MKP1 expression and attenuating JNK-mediated apoptosis by RIP1 for cisplatin resistance through miR-940 inhibition. Oncotarget 5:1304-14
Chen, W; Wang, Q; Bai, L et al. (2014) RIP1 maintains DNA integrity and cell proliferation by regulating PGC-1?-mediated mitochondrial oxidative phosphorylation and glycolysis. Cell Death Differ 21:1061-70
He, W; Wang, Q; Srinivasan, B et al. (2014) A JNK-mediated autophagy pathway that triggers c-IAP degradation and necroptosis for anticancer chemotherapy. Oncogene 33:3004-13
Wang, Qiong; Chen, Wenshu; Xu, Xiuling et al. (2013) RIP1 potentiates BPDE-induced transformation in human bronchial epithelial cells through catalase-mediated suppression of excessive reactive oxygen species. Carcinogenesis 34:2119-28
Xu, Xiuling; Bai, Lang; Chen, Wenshu et al. (2012) MUC1 contributes to BPDE-induced human bronchial epithelial cell transformation through facilitating EGFR activation. PLoS One 7:e33846
Bai, Lang; Xu, Shanling; Chen, Wenshu et al. (2011) Blocking NF-?B and Akt by Hsp90 inhibition sensitizes Smac mimetic compound 3-induced extrinsic apoptosis pathway and results in synergistic cancer cell death. Apoptosis 16:45-54
Chen, Wenshu; Li, Zi; Bai, Lang et al. (2011) NF-kappaB in lung cancer, a carcinogenesis mediator and a prevention and therapy target. Front Biosci (Landmark Ed) 16:1172-85

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