Rationale: HNSCC are particularly aggressive due to high incidence of recurrence and distant metastasis. Majority of HNSCC are detected and treated at stage III/IV. For this reason, despite significant advances in surgery, radiation therapy and chemotherapy, the 5-year/50% survival rate of HNSCC has not improved significantly over the past 35 years. The minority and medically underserved populations lack early detection, which contribute to a high death rate. A clearer understanding of the molecular mechanisms underlying aggressive progression of HNSCC is critical for early detection and development of effective therapeutic intervention against this deadly disease. This proposal focuses on the regulation of Hypoxia-signaling by DDB2 in HNSCC. DDB2 (XPE) is a sensor of DNA damage and it plays an important role in Global Genomic Repair (GG-NER). Interestingly, loss of DDB2 expression in HNSCC coincides with metastatic progression and reduced survival. Our recent studies show that DDB2 blocks mRNA expression of HIF1? and key HIF1?-target genes in HNSCC cells. HIF1? mediates key transcriptional responses to hypoxia. Specifically, high HIF1? in tumors is associated with a more aggressive tumor phenotype and worse survival in HNSCC and a 15-gene hypoxia profile has demonstrated to have prognostic significance in HNSCC. We also observed that DDB2 constitutively represses the EMT regulators Snail and Zeb1 and EMT markers, Vimentin, E-Cad and N-Cad in SCC9 and SCC15 HNSCC cells. While recent meta-analysis of gene expression data from HNSCC characterized the hypoxia-type and the mesenchymal type (EMT-type) as two most aggressive cancer clusters, the mechanism of de-regulation is poorly understood. Our hypothesis is that DDB2 plays a major defensive role against hypoxia-related pro-metastatic changes in HNSCC. The loss of DDB2 observed in high-grade/metastatic HNSCC brings about high-levels of HIF1?-activity, and expression of the HIF1?-target genes that are normally activated during hypoxia. The proposed studies will allow us to describe a new arm of hypoxia signaling in HNSCC.
The Specific Aims are to (1) Investigate whether DDB2 opposes hypoxia response in HNSCC cells (2) Investigate the expression patterns of DDB2 and HIF1? in HNSCC TumorMicroarrays (3) Investigate whether loss of DDB2 drives aggressive Oral tumors in mice These studies will have exciting implications about identification of reduced level of DDB2 as a potential biomarker for progression of HNSCC, as well as towards therapy of aggressive cancers because DDB2 expression can be stimulated by PEITC.
Squamous Cell Carcinomas in the Oral/Head & Neck region (HNSCC) are particularly aggressive due to high incidence of recurrence and distant metastasis. HNSCC is the eighth most common malignancy and an estimated 600,000 new cases are diagnosed worldwide each year, with more than 350,000 deaths annually. Detection of HNSCC at stage I/II have excellent survival rate, however, the vast majority (>90%) of HNSCCs are detected and treated at stageIII/IV. For this reason, despite significant advances in surgery, radiation therapy and chemotherapy, the 5- year/50% survival rate has not improved significantly over the past 35 years. The minority and medically underserved populations are most affected due to the lack of early detection. For this reason, there is profound need for understanding the mechanisms of progression towards aggressive metastatic lesions and development of useful prognostic biomarkers in HNSCC for early detection. Elevated tumor hypoxia and expression of HIF1? (hypoxia inducible factor) has been associated with poor prognosis and correlates with reduced survival for patients with HNSCC. DDB2 is a sensor of DNA damage and recently we observed that DDB2 blocks expression of HIF1? in HNSCC cells. DDB2 also represses key HIF1?-target genes including the angiogenic factor VEGF, and the EMT regulators Snail and Zeb1 in HNSCC cells. Interestingly, loss of the DDB2 expression in HNSCC coincides with metastatic progression and reduced survival. The studies in this proposal will investigate regulation of the hypoxia-signaling pathway by DDB2 that drives HNSCC progression and metastasis. These studies will have exciting implications about identification of reduced level of DDB2 as a potential biomarker for progression of HNSCC.
