Head and neck squamous cell carcinoma (HNSCC) is the most common cancer in the oral cavity, oropharynx, head and neck. It is the sixth most common cancer type, and is frequently associated with low survival and high morbidity rates. The invasive growth is a complex process which directs cells to dissociate, degrade the surrounding matrix, infiltrate adjacent tissues and survive. It plays a critical role in the development of invasive HNSCC from epithelial dysplasia and carcinoma in situ. Works from us and others have demonstrated that nuclear factor-kappa B (NF-?B) plays an important role in the development of invasive HNSCC. NF-?B has been found to be constitutively activated in human primary HNSCC tissues. NF-?B target genes, including tumor necrosis factor (TNF), Interleukine-8 (IL-8), IL-6 and Cox-2, are highly expressed in HNSCC. Despite significant progress has been made in understanding of NF-?B activation, it remains unknown about how NF-?B activities are increased in HNSCC. Peroxisome proliferator-activated receptor ? coactivators 1? (PGC-1?) is a master regulator of mitochondrial biogenesis and oxidative metabolism in skeletal muscle, liver, brain and heart. It is well known that loss of PGC-1??is associated with increased ROS, aging and chronic inflammation. In this competing renewal, our preliminary studies demonstrated that PGC-1??expression was significantly reduced in HNSCC tissues compared to normal adjacent tissues and was inversely correlated with NF-?B activation. We found that loss of PGC-1??significantly promotes the development of invasive HNSCC by activating NF-?B in vivo using genetic approaches. More interestingly, we found that PGC-1?/NF-?B signaling might epigenetically promote HNSCC cell invasion and survival by inducing the demethylase Jumonji domain containing 3 (JMJD3). Based on these exciting preliminary studies, we hypothesize that PGC-1? might intrinsically control HNSCC development by modulating NF-?B activation. Loss of PGC-1??might be one of the key factors which contribute to increased NF-?B activities in HNSCC. To test our hypothesis, we propose three specific aims: 1) Determine whether loss of PGC-1??promotes the development of invasive HNSCC in vivo by activating NF-?B; 2) Explore the molecular mechanism by which PGC-1??controls NF-?B activation and determine whether the restoration of PGC-1??suppresse human HNSCC invasive growth by inhibiting NF-?B in vivo; and 3) Determine whether activation of NF-?B by loss of PGC-1??epigenetically promotes HNSCC invasion and survival by promoting JMJD3 expression. New findings from this application might not only elucidate the molecular mechanism of NF-?B activation in HNSCC, but also help to develop novel therapeutic strategies for treatment and prevention of HNSCC.
Head and neck squamous cell carcinoma (HNSCC) is a very malignant cancer with poor prognosis due to its invasive growth. In this application, we will examine how the transcription co-activator PGC-1??regulates the development of invasive HNSCC through nuclear factor-kappa B (NF-?B). Discoveries from this study will help us to develop novel strategies for treating HNSCC and other human cancers.
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