The major goal of this application is to identify the molecular and genetic determinants which control/promote the invasive growth and metastasis of head and neck squamous cell carcinomas (HNSCC). The poor prognosis of patients with HNSCC is due to the high invasive growth potential of these tumors, resulting in early regional lymph node and subsequent distant metastasis. The invasive growth, which is instrumental in invasion and metastasis of HNSCC, is a complex multistage process in which cell proliferation combines with cell-cell dissociation and movement, matrix degradation and survival. Although the gene expression profiling has provided important information regarding HNSCC-associated genes, little is known about the molecular and genetic determinants which are associated with the invasive growth of HNSCC. We hypothesize that the invasive growth of HNSCC may be controlled by a group of unique genes (invasive genes). Since clinical studies have found that the abnormal activation of the hepatocyte growth factor (HGF)/c-Met signaling pathway is associated with the invasion and metastasis of HNSCC and since HGF potently stimulates the invasive growth of HNSCC in several experimental models, in this application, we propose to employ functional genomic approaches to dissect its signaling network and to identify its downstream effectors/molecules.
In Aim 1, we propose to identify HGF-induced genes which play an important role in the invasive growth and survival of HNSCC using microan'ay analysis.
In Aim 2, we attempt to screen HGF-induced genes which promote invasive growth using a combination of functional assays and cDNA expression library on a genome-wide basis.
In Aim 3, we propose to identify novel invasive genes from the invasive/metastatic human tumors. Using tissue microarray, we will confirm whether the expression of newly identified genes is associated with HNSCC invasive growth and metastasis, thereby developing a novel molecular signature of the invasive gene expression for HNSCC. The novel findings from these studies may help us to understand the molecular mechanisms of HNSCC invasive growth and to develop new strategies for the diagnosis, prevention and treatment of HNSCC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE015964-03
Application #
7015036
Study Section
Special Emphasis Panel (ZDE1-PZ (15))
Program Officer
Shirazi, Yasaman
Project Start
2004-04-01
Project End
2009-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
3
Fiscal Year
2006
Total Cost
$373,511
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biology
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Plouffe, Steven W; Lin, Kimberly C; Moore 3rd, Jerrell L et al. (2018) The Hippo pathway effector proteins YAP and TAZ have both distinct and overlapping functions in the cell. J Biol Chem 293:11230-11240
Li, Jiong; Yu, Bo; Deng, Peng et al. (2017) KDM3 epigenetically controls tumorigenic potentials of human colorectal cancer stem cells through Wnt/?-catenin signalling. Nat Commun 8:15146
Lin, Kimberly C; Park, Hyun Woo; Guan, Kun-Liang (2017) Regulation of the Hippo Pathway Transcription Factor TEAD. Trends Biochem Sci 42:862-872
Cheng, Yingduan; Wang, Yi; Li, Jiong et al. (2017) A novel read-through transcript JMJD7-PLA2G4B regulates head and neck squamous cell carcinoma cell proliferation and survival. Oncotarget 8:1972-1982
Ramadoss, S; Guo, G; Wang, C-Y (2017) Lysine demethylase KDM3A regulates breast cancer cell invasion and apoptosis by targeting histone and the non-histone protein p53. Oncogene 36:47-59
Chen, Demeng; Wu, Mansi; Li, Yang et al. (2017) Targeting BMI1+ Cancer Stem Cells Overcomes Chemoresistance and Inhibits Metastases in Squamous Cell Carcinoma. Cell Stem Cell 20:621-634.e6
Lin, Kimberly C; Moroishi, Toshiro; Meng, Zhipeng et al. (2017) Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation. Nat Cell Biol 19:996-1002
Fu, Vivian; Plouffe, Steven W; Guan, Kun-Liang (2017) The Hippo pathway in organ development, homeostasis, and regeneration. Curr Opin Cell Biol 49:99-107
Plouffe, Steven W; Meng, Zhipeng; Lin, Kimberly C et al. (2016) Characterization of Hippo Pathway Components by Gene Inactivation. Mol Cell 64:993-1008
Chang, Insoon; Wang, Cun-Yu (2016) Inhibition of HDAC6 Protein Enhances Bortezomib-induced Apoptosis in Head and Neck Squamous Cell Carcinoma (HNSCC) by Reducing Autophagy. J Biol Chem 291:18199-209

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