The long-term objective of this application is to identify the molecular and genetic determinants which promote the invasive growth and metastasis of head and neck squamous cell carcinomas (SCC). The poor prognosis of patients with SCC 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 SCC, is a complex multistage process in which cell-cell dissociation combines with movement, matrix degradation and survival. During the last funding period, we have demonstrated that hepatocyte growth factor (HGF)/c-Met inhibits anoikis induced by a loss of cell-matrix interaction and promotes SCC progression. In this competing renewal, we hypothesize that HGF/c-Met plays an integral role in the invasive growth by stimulating transcription of invasive genes. We propose to employ molecular and genetic approaches to examine how HGF-induced genes promote the invasive growth of SCC cells and how these genes are epigenetically regulated in SCC cells. There are four specific aims.
In Aim 1, we will examine how Mcl-1 induced by HGF inhibits anoikis which is critical for the invasive SCC cells and whether c-Met inhibitors abolish anoikis resistance induced by HGF.
In Aim 2, we will determine whether the AP-1 family member Fra-1 plays a role in invasive growth of SCC cells induced by HGF and is associated with SCC metastasis.
In Aim 3, we will explore how the transcription co-activators are recruited to the Fra-1 promoter to activate transcription.
In Aim 4, we will explore how histone methylation and chromatin remodeling regulate HGF-stimulating transcription and invasive growth. The novel findings from this application may have important implications in developing therapeutic strategies to interfere with the invasive growth and metastasis of SCC and other human cancers.

Public Health Relevance

Squamous cell carcinoma (SCC) is the most common cancer of the head and neck. Advanced SCC with metastasis is often incurable and possesses poor prognosis. Hepatocyte growth factor (HGF) has been found to play an important role in SCC metastasis by stimulating the invasive growth of SCC cells. The long-term objectives of this application are to understand why head and neck SCC and other malignant cancers frequently leave their original site and spread to local and distant organs. In this application, we will examine how HGF stimulates invasion and survival of SCC cells by inducing new gene expression. We will determine whether HGF target genes are abnormally expressed in human SCC tumors and are associated with metastasis. New findings from this study will help us to develop novel strategies for treating SCC and other human cancers.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Venkatachalam, Sundaresan
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University of California Los Angeles
Schools of Dentistry
Los Angeles
United States
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Ding, Xiangming; Pan, Hongya; Li, Jiong et al. (2013) Epigenetic activation of AP1 promotes squamous cell carcinoma metastasis. Sci Signal 6:ra28.1-13, S0-15
Ding, Xiangming; Park, Serk In; McCauley, Laurie K et al. (2013) Signaling between transforming growth factor * (TGF-*) and transcription factor SNAI2 represses expression of microRNA miR-203 to promote epithelial-mesenchymal transition and tumor metastasis. J Biol Chem 288:10241-53
Zhao, Bin; Li, Li; Wang, Lloyd et al. (2012) Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev 26:54-68
Ramadoss, Sivakumar; Li, Jiong; Ding, Xiangming et al. (2011) Transducin ?-like protein 1 recruits nuclear factor ?B to the target gene promoter for transcriptional activation. Mol Cell Biol 31:924-34
Song, Jun; Chang, Insoon; Chen, Zhuo et al. (2010) Characterization of side populations in HNSCC: highly invasive, chemoresistant and abnormal Wnt signaling. PLoS One 5:e11456
Tang, Eric D; Wang, Cun-Yu (2010) TRAF5 is a downstream target of MAVS in antiviral innate immune signaling. PLoS One 5:e9172
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Rehman, Aasia O; Wang, Cun-yu (2009) CXCL12/SDF-1 alpha activates NF-kappaB and promotes oral cancer invasion through the Carma3/Bcl10/Malt1 complex. Int J Oral Sci 1:105-18
Rehman, Aasia O; Wang, Cun-Yu (2008) SDF-1alpha promotes invasion of head and neck squamous cell carcinoma by activating NF-kappaB. J Biol Chem 283:19888-94
Fribley, Andrew; Wang, Cun-Yu (2006) Proteasome inhibitor induces apoptosis through induction of endoplasmic reticulum stress. Cancer Biol Ther 5:745-8

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