Lung cancer remains the leading cause of cancer death in the world for both men and women, and non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer. Nearly 80% of lung cancer is diagnosed at an advanced inoperable stage, and current systemic therapy offers only modest benefits for lung cancer patients. The overall goal of this study is to determine the role of ?-catenin independent (i.e. non-canonical) Wnt signaling on the initiation and promotion of NSCLC. Our findings to date suggest two seemingly unrelated Wnt 7a functions: 1) that Wnt 7a acts as a tumor suppressor in normal lung epithelia, and 2) that activation of Wnt 7a activates ?-catenin independent (non-canonical) Wnt signaling through Fzd9, inducing activation of the tumor suppressor gene PPAR?. In previous work, we have demonstrated that Wnt 7a and/or Fzd 9 expression is frequently reduced in NSCLC, and that the loss of Wnt 7a and/or Fzd 9 is strongly associated with epithelial to mesenchymal transition (EMT), loss of cellular polarity, and increased susceptibility to lung carcinogenesis in mice. Based on these findings, we hypothesize that Wnt 7a/Fzd9 signaling plays a novel role in establishing and/or maintaining cell polarity, and functions as a tumor suppressor in the lung epithelium by regulating non- canonical Wnt (?-catenin independent) signaling. Moreover, our recent finding of frequent promoter methylation of Wnt 7a in human lung cancer makes Wnt 7a a potentially attractive future therapeutic target in the treatment of NSCLC.

Public Health Relevance

Lung cancer is the leading cause of cancer death for both men and women in the United States. In fact, more deaths will occur this year due to lung cancer than breast, prostate, and colorectal cancers combined. The experimental strategies outlined in this project are designed to evaluate the contribution of the non-canonical Wnt pathway to lung cancer and to identify genetic targets of this pathway that could be used to develop potential small molecular therapeutic targets for the treatment of lung cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138528-02
Application #
8137632
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Woodhouse, Elizabeth
Project Start
2010-09-02
Project End
2015-07-31
Budget Start
2011-09-23
Budget End
2012-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$300,039
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Bikkavilli, Rama Kamesh; Zerayesus, Sereke Adam; Van Scoyk, Michelle et al. (2017) K-homology splicing regulatory protein (KSRP) promotes post-transcriptional destabilization of Spry4 transcripts in non-small cell lung cancer. J Biol Chem 292:7423-7434
Bikkavilli, R K; Avasarala, S; Van Scoyk, M et al. (2015) Wnt7a is a novel inducer of ?-catenin-independent tumor-suppressive cellular senescence in lung cancer. Oncogene 34:5317-28
Sechler, Marybeth; Borowicz, Stanley; Van Scoyk, Michelle et al. (2015) Novel Role for ?-Catenin in the Regulation of Cancer Cell Migration via the Induction of Hepatocyte Growth Factor Activator Inhibitor Type 1 (HAI-1). J Biol Chem 290:15610-20
Parrish, J K; Sechler, M; Winn, R A et al. (2015) The histone demethylase KDM3A is a microRNA-22-regulated tumor promoter in Ewing Sarcoma. Oncogene 34:257-62
Bikkavilli, Rama Kamesh; Avasarala, Sreedevi; Van Scoyk, Michelle et al. (2014) In vitro methylation assay to study protein arginine methylation. J Vis Exp :e51997
Avasarala, Sreedevi; Bikkavilli, Rama Kamesh; Van Scoyk, Michelle et al. (2013) Heterotrimeric G-protein, G?16, is a critical downstream effector of non-canonical Wnt signaling and a potent inhibitor of transformed cell growth in non small cell lung cancer. PLoS One 8:e76895
Bikkavilli, Rama Kamesh; Avasarala, Sreedevi; Vanscoyk, Michelle et al. (2012) Dishevelled3 is a novel arginine methyl transferase substrate. Sci Rep 2:805
Tennis, Meredith A; Vanscoyk, Michelle M; Wilson, Lora A et al. (2012) Methylation of Wnt7a is modulated by DNMT1 and cigarette smoke condensate in non-small cell lung cancer. PLoS One 7:e32921
Tennis, Meredith A; Van Scoyk, Michelle; Heasley, Lynn E et al. (2010) Prostacyclin inhibits non-small cell lung cancer growth by a frizzled 9-dependent pathway that is blocked by secreted frizzled-related protein 1. Neoplasia 12:244-53
Choudhary, Rashmi; Li, Howard; Winn, Robert A et al. (2010) Peroxisome proliferator-activated receptor-gamma inhibits transformed growth of non-small cell lung cancer cells through selective suppression of Snail. Neoplasia 12:224-34

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