Signal and Transcription Factor Network interactions in Head and Neck Cancer

头颈癌中的信号和转录因子网络相互作用

• 批准号: 9353064
• 负责人: CARTER VAN WAES
• 金额: $ 63.06万
• 依托单位: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9353064
• 关键词: Adverse effects; Affect; Agonist; Apoptosis; Apoptosis Inhibitor; BIRC2 gene; BIRC4 gene; Baculoviruses; Bioinformatics; Caspase; Cell Cycle Arrest; Cell Death; Cell Line; Cells; Cessation of life; Clinical Research; DNA Fragmentation; DNA Sequence Alteration; Death Domain; Deglutition; Development; Diagnosis; Epithelial; Exhibits; Family; Gene Expression; Gene Transfer; Genes; Genomics; Goals; Growth; Growth Factor Gene; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Heterogeneity; Human; Immune response; In Vitro; Inflammatory; Larynx; Ligands; M cell; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; NF-kappa B; Nature; Normal tissue morphology; Oncogenes; Oral cavity; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharyngeal structure; Phosphotransferases; Play; Preclinical Testing; Prevention therapy; Progressive Disease; Quality of life; RIPK1 gene; Radiation; Radiosurgery; Recurrent disease; Regulation; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Speech; TNF gene; TNFSF10 gene; TP53 gene; The Cancer Genome Atlas; Tumor Suppressor Proteins; Voice; Western Blotting; Xenograft Model; activating transcription factor; base; chemotherapy; exome sequencing; in vivo; inhibitor/antagonist; knock-down; malignant phenotype; mimetics; multicatalytic endopeptidase complex; novel; outcome forecast; overexpression; preclinical study; protein biomarkers; research clinical testing; resistance mechanism; response to injury; targeted agent; therapy resistant; transcription factor; tumor; tumor growth; vector

Growth factor and inflammatory signal networks are implicated in promoting cancer development, including human head and neck squamous cell carcinomas (HNSCC). The PI3K kinases important in growth signaling are implicated in modulating the reciprocal regulation of NF-kappaB/REL oncogene and TP53/63/73 family tumor suppressor function and their role in the malignant phenotype. Our findings suggest signal regulation coordinating NF-kB, TP53, p63 and p73 interactions and function may be important in pathogenesis and as targets for prevention and therapy. Genes identified as part of the Cancer Genome Atlas Network study of head and neck cancer (Nature , 2015) are implicated in NF-kappaB and cell death pathways.Comparison of tumors from the Cancer Genome Atlas (TCGA) reveals that head and neck squamous cell carcinomas (HNSCC) harbor the most frequent genomic amplifications of Fas-associated death domain (FADD), with or without Baculovirus Inhibitor of Apoptosis repeat containing BIRC2 (cIAP1), affecting 30% of patients in association with worse prognosis. We identified HNSCC cell lines harboring FADD/BIRC2 amplifications and overexpression by exome sequencing, RT-PCR and Western blot. In vitro, FADD or BIRC2 siRNA knockdown inhibited HNSCC displaying amplification and increased expression of these genes, supporting their functional importance in promoting proliferation. Birinapant, a novel SMAC mimetic, sensitized multiple HNSCC lines to cell death by agonists TNFalpha or TRAIL, and inhibited cIAP1>XIAP>IAP2. Combination of birinapant and TNF induced sub-G0 DNA fragmentation in sensitive lines, and birinapant alone also induced significant G2/M cell cycle arrest and cell death in UM-SCC-46 cells. Gene transfer and expression of FADD sensitized resistant UM-SCC-38 cells lacking FADD amplification to birinapant and TNFalpha, supporting a role for FADD in sensitization to IAP inhibitor and death ligands. HNSCC varied in mechanisms of cell death, as indicated by reversal by inhibitors or protein markers of caspase-dependent apoptosis and/or RIPK1/MLKL-mediated necroptosis. In vivo, birinapant inhibited tumor growth and enhanced radiation induced TNFalpha, tumor responses, and host survival in UM-SCC-46 and -11B xenograft models displaying amplification and overexpression of FADD+/-BIRC2. These findings suggest that combination of SMAC mimetics such as birinapant plus radiation may be particularly active in HNSCC, which harbor frequent FADD/BIRC2 genomic alterations.

生长因子和炎症信号网络与促进癌症发展有关，包括人头和颈部鳞状细胞癌（HNSCC）。在生长信号传导中重要的PI3K激酶与调节NF-KAPPAB/RER ORCOGENE和TP53/63/63/73家庭肿瘤抑制器功能及其在恶性表型中的作用的相互调控有关。我们的发现表明，信号调节协调NF-KB，TP53，P63和P73相互作用以及功能在发病机理中可能很重要，并且是预防和治疗的靶标。 头颈癌的癌症基因组网络研究的一部分（自然，2015年）与NF-kappab和细胞死亡途径有关。含有BIRC2的凋亡重复抑制剂（CIAP1），影响30％的患者与预后较差。我们确定了具有FADD/BIRC2扩增的HNSCC细胞系，并通过外显子组测序，RT-PCR和Western blot进行过表达。在体外，FADD或BIRC2 siRNA敲低抑制了HNSCC，显示出扩增和增加这些基因的表达，从而支持它们在促进增殖中的功能重要性。 Birinapant是一种新型的Smac Mimetic，将多个HNSCC线敏感到激动剂TNFALPHA或TRAIL的细胞死亡，并抑制CIAP1> XIAP> IAP2。 Birinapant和TNF在敏感线中诱导的亚G0 DNA片段化的组合，单独的Birinapant还诱导了UM-SCC-46细胞中明显的G2/M细胞周期停滞和细胞死亡。 FADD敏感性的抗性UM-SCC-38细胞的基因转移和表达缺乏FADD扩增对Birinapant和Tnfalpha，这支持FADD在对IAP抑制剂和死亡配体敏化中的作用。 HNSCC的细胞死亡机制有所不同，如caspase依赖性细胞凋亡的抑制剂或蛋白质标记和/或RIPK1/MLKL介导的坏死性坏死性的逆转所表明的那样。在体内，Birinapant抑制了肿瘤的生长，并增强了辐射诱导的TNFALPHA，肿瘤反应以及UM-SCC-46和-11B异种移植模型，显示出FADD +//- BIRC2的扩增和过表达。这些发现表明，在HNSCC中，SMAC模拟物（例如Birinapant Plus辐射）的组合可能特别活跃，HNSCC具有频繁的FADD/BIRC2基因组改变。