Molecular and Genetic Determinants of Invasion in HNSCC

HNSCC 侵袭的分子和遗传决定因素

• 批准号: 9304784
• 负责人: CUN-YU WANG
• 金额: $ 49.68万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9304784
• 关键词: Age; Aging; Alcohol abuse; Apoptosis; Apoptotic; Biogenesis; Biological Assay; Brain; Carcinoma; Carcinoma in Situ; Caspase; Cell Line; Cell Respiration; Cells; Chemopreventive Agent; Chronic; Complex; DNA Methylation; Development; Environment; Enzymes; Epigenetic Process; Gene Targeting; Genes; Genetic; Genetic Determinism; Growth; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Heart; Human; Human papilloma virus infection; Immunocompetent; Inflammation; Interleukin-6; Intraepithelial Neoplasia; Knockout Mice; Liver; MAP3K7 gene; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Metastatic Neoplasm to Lymph Nodes; Methylation; Mitochondria; Molecular; Molecular Genetics; Molecular Profiling; Morbidity - disease rate; Mus; NF-kappa B; Nitroquinolines; Nuclear; Oral; Oral cavity; Oropharyngeal; Oxidative Stress; PPAR gamma; Patients; Phosphorylation; Play; Population; Prevention; Process; Risk Factors; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Smoking; Structure; Survival Rate; TNF gene; Testing; Tissues; Transcription Coactivator; Transgenic Mice; Trauma; Western Blotting; Work; base; cancer type; chromatin immunoprecipitation; genetic approach; histone demethylase; in vivo; keratinocyte; knock-down; loss of function; mouse model; novel; novel strategies; novel therapeutics; outcome forecast; p65; promoter; public health relevance; restoration; small molecule inhibitor; transcriptome sequencing; treatment strategy

 DESCRIPTION (provided by applicant): 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-κB) plays an important role in the development of invasive HNSCC. NF-κB has been found to be constitutively activated in human primary HNSCC tissues. NF-κB 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-κB activation, it remains unknown about how NF-κB activities are increased in HNSCC. Peroxisome proliferator-activated receptor γ coactivators 1α (PGC-1α) 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-κB activation. We found that loss of PGC-1significantly promotes the development of invasive HNSCC by activating NF-κB in vivo using genetic approaches. More interestingly, we found that PGC-1/NF-κB 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-1α might intrinsically control HNSCC development by modulating NF-κB activation. Loss of PGC-1might be one of the key factors which contribute to increased NF-κB 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-κB; 2) Explore the molecular mechanism by which PGC-1controls NF-κB activation and determine whether the restoration of PGC-1suppresse human HNSCC invasive growth by inhibiting NF-κB in vivo; and 3) Determine whether activation of NF-κB 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-κB activation in HNSCC, but also help to develop novel therapeutic strategies for treatment and prevention of HNSCC.

 描述（由适用提供）：头部和颈部鳞状细胞癌（HNSCC）是口腔，口咽，头颈最常见的癌症。它是第六种最常见的癌症类型，并且经常与低生存率和高发病率有关。侵入性生长是一个复杂的过程，它指导细胞解离，降解周围的基质，浸润相邻组织并存活。它在来自上皮异常增生和癌症的侵入性HNSCC的发展中起着至关重要的作用。我们和其他人的作品表明，核因子-KAPPA B（NF-κB）在侵入性HNSCC的发展中起着重要作用。已经发现NF-κB在人类原代HNSCC组织中持续激活。 NF-κB靶基因，包括肿瘤坏死因子（TNF），白介碱-8（IL-8），IL-6和COX-2，在HNSCC中高度表达。尽管在理解NF-κB激活方面取得了重大进展，但HNSCC中NF-κB活性如何增加仍然未知。过氧化物组增殖物激活的受体γ共激活因子1α（PGC-1α）是骨骼肌，肝脏，脑和心脏中线粒体生物发生和氧化代谢的主要调节剂。众所周知，PGC-1的丧失与ROS，衰老和慢性影响增加有关。在这种竞争的更新中，我们的初步研究表明，与正常的相邻组织相比，HNSCC组织中的PGC-1显着降低，并且与NF-κB激活成反比。我们发现，PGC-1的丧失通过遗传方法在体内激活NF-κB来促进侵入性HNSCC的发展。更有趣的是，我们发现PGC-1/NF-κB信号传导可能通过诱导含有3个（JMJD3）的脱甲基二甲基Jumonji结构域诱导脱甲基酶Jumonji结构域来表观遗传促进HNSCC细胞侵袭和存活。基于这些令人兴奋的初步研究，我们假设PGC-1α可能通过调节NF-κB激活来内在地控制HNSCC的发展。 PGC-1的丧失是可能导致HNSCC中NF-κB活性增加的关键因素之一。为了检验我们的假设，我们提出了三个具体目的：1）确定PGC-1的丧失是否通过激活NF-κB来提高体内侵入性HNSCC的发展； 2）探索PGC-1控制NF-κB激活的分子机制，并确定PGC-1Suppresse人类HNSCC侵入性生长是否通过体内抑制NF-κB来恢复； 3）确定通过损失PGC-1的激活是否通过促进JMJD3表达来促进HNSCC侵袭和存活。该应用的新发现不仅可能阐明HNSCC中NF-κB激活的分子机制，而且还有助于开发新的治疗策略，以治疗和预防HNSCC。