Our long-term goal is to understand molecular mechanisms underlying novel tumor suppressor genes Slit and USP33. Our previous work and preliminary data suggest that a prototypical neuronal repellent, Slit, is an important tumor suppressor for lung cancer and that Slit expression predicts better prognosis in lung cancer patients. To dissect Slit signaling pathways and examine mechanisms underlying tumor suppression in lung cancer, we examined how signal-transducing molecules interacted with Slit receptor Roundabout (Robo). We identified the deubiquitinating enzyme, USP33, as a critical component in Slit-Robo signaling pathway(s) in lung cancer. This proposal aims to examine Slit-Robo-USP33 mediated tumor suppression in lung cancer using molecular, biochemical and cell biological methods in combination with animal models and sequence analyses of human lung cancer samples. Our pilot deep-sequencing studies support the tumor suppressive function of Slit-Robo- USP33 pathway and the involvement of the downstream signaling molecules. We have established both in vitro assays and animal models to study the role of this newly uncovered tumor suppression pathway in lung cancer development. We plan to use these integrated molecular, cellular and genetic approaches to define the role of Slit-Robo signaling in suppressing lung cancer. Our proposed work will help elucidate molecular mechanisms underlying Slit and USP33 tumor suppressors and determine the role of genetic variations in Slit or USP33 and their downstream genes in development of human lung cancer.

Public Health Relevance

Our long-term goal is to identify novel tumor suppressor genes in lung cancer and to elucidate their mechanisms to suppress lung tumorigenesis and metastasis. Our recent work suggests that neuronal guidance protein Slit, its receptor Robo and downstream signaling molecules, including a deubiquitinating enzyme USP33, play critical roles in suppressing lung cancer. Using an integrated molecular, cellular, animal model and genetic approach to determine the role of Slit and USP33 in lung cancer, our study will not only lead to a better understanding of tumor suppression mechanisms of Slit and USP33 in lung cancer but also help identify new therapeutic targets for this fatal disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA175360-01A1
Application #
8632559
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Ault, Grace S
Project Start
2014-03-07
Project End
2019-02-28
Budget Start
2014-03-07
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$456,700
Indirect Cost
$100,006
Name
Northwestern University Chicago
Department
Neurology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Huang, Zhaohui; Wen, Pushuai; Kong, Ruirui et al. (2015) USP33 mediates Slit-Robo signaling in inhibiting colorectal cancer cell migration. Int J Cancer 136:1792-802
Wen, Pushuai; Kong, Ruirui; Liu, Jianghong et al. (2014) USP33, a new player in lung cancer, mediates Slit-Robo signaling. Protein Cell 5:704-13