EGFR Signaling As the Nexus for HPV Oncogene Regulation

EGFR 信号传导作为 HPV 癌基因调控的纽带

• 批准号: 9792241
• 负责人: Adrian J. Luna Leon
• 金额: $ 4.07万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-11 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9792241
• 关键词: 3-Dimensional; Adherence; Antiviral Agents; Basal Cell; Basic Science; Benign; Biological Assay; Biological Markers; Carcinoma; Cell Line; Cells; Cervical Intraepithelial Neoplasia; Cervix carcinoma; Contact Inhibition; Data; Desmosomes; Disease; Double Stranded DNA Virus; EGF gene; Engineering; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epithelial; Epithelial Cells; Epithelium; Etiology; Gap Junctions; Gene Expression; Genetic; Genetic Transcription; Genome; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; In Vitro; Infection; Inhibition of Apoptosis; Intraepithelial Neoplasia; Knowledge; Lead; Lesion; Life Cycle Stages; MEKs; Malignant - descriptor; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Malignant neoplasm of anus; Molecular; Neoplasms; Oncogenes; Oncogenic; Oncoproteins; Oropharyngeal; Outcome; Papillomavirus Transforming Protein E6; Pathway interactions; Pharmacology; Phenotype; Process; Protein Array; Proteins; Receptor Activation; Receptor Signaling; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Squamous Epithelium; Squamous cell carcinoma; Subfamily lentivirinae; System; Testing; Tissue Differentiation; Tissues; Transcription Factor AP-1; Tropism; Viral; Viral Oncogene; Viral Physiology; Virion; Virus; Work; base; cancer cell; carcinogenesis; cellular targeting; chromatin immunoprecipitation; daughter cell; desmoglein 1; desmoglein 2; epidemiologic data; human papilloma virus oncogene; in vivo; inhibitor/antagonist; innovation; interest; monolayer; neoplastic; neoplastic cell; novel; overexpression; public health relevance; theories; therapeutic target; tissue culture; transcription factor; tumor; tumor progression; virtual

ABSTRACT A subset of human papillomaviruses (HPVs) cause nearly 5% of the world’s cancers. The HPVs are small non-enveloped, double-stranded DNA viruses that have a tropism for squamous epithelium. HPVs are completely dependent on normal epithelial differentiation for completion of their replicative cycles. HPVs infect basal epithelial cells where they establish extra-chromosomal replication of their genomes. As infected basal cells divide and daughter cells move to the upper cell layers, the expression of the early viral E6 and E7 proteins promote proliferation of the suprabasal epithelial layers. This results in a phenotype of epithelial dysplasia and expansion of HPV infected cells. Broadly, two outcomes become possible. One outcome is a productive infection. Herein, cellular differentiation ensues, viral E6 and E7 gene expression is suppressed, and HPV late gene expression is activated to complete the virus life cycle and yield progeny virions. In the second outcome, the maintained (deregulated) expression of the E6 and E7 proteins continues to promote proliferation and inhibit tissue differentiation. However, little is known about how HPV oncogene expression is regulated during the process of epithelial tissue differentiation or how regulation is lost during carcinogenesis. To study HPV oncogene regulation, we are using cell lines that grow as neoplastic tissues able to recapitulate the entire HPV life cycle in organotypic epithelial tissue cultures. Our data indicate that epidermal growth factor receptor (EGFR) signaling and contact inhibition influence HPV oncogene expression. We find that HPV oncogene expression is transcriptionally down-regulated concomitant with suppression of EGFR signaling as cells become increasingly confluent. Furthermore, EGF stimulation of confluent cells restores E6 and E7 expression, but this can be hindered with inhibitors of EGFR, MEK, or ERK. In this proposal I will define the effectors of EGFR that regulate E6/E7 transcription and will determine the mechanism by which EGFR signaling is influenced by epithelial interactions to effect viral oncogene transcription.

摘要 人类乳头瘤病毒(HPV)的一个亚组导致了世界上近5%的癌症。人乳头瘤病毒很小 无包膜的双链DNA病毒，偏向于鳞状上皮。HPV是 完全依赖于正常的上皮分化来完成它们的复制周期。人乳头瘤病毒感染 基底上皮细胞，在那里它们建立其基因组的染色体外复制。作为受感染的基础 细胞分裂，子细胞向上层细胞移动，早期病毒E6和E7的表达 蛋白质促进基底上皮层的增殖。这导致了上皮细胞的表型 HPV感染细胞的异常增殖和扩增。总的来说，有两种结果成为可能。一种结果是 生殖性感染。在此，细胞分化随之而来，病毒E6和E7基因的表达受到抑制， 而HPV晚期基因的表达被激活，以完成病毒的生命周期并产生后代病毒粒子。在 第二个结果是，E6和E7蛋白的持续(解除调控)表达继续促进 增殖和抑制组织分化。然而，关于人乳头瘤病毒癌基因如何 在上皮组织分化过程中或如何失去调控的过程中表达受到调控 在癌变过程中。为了研究hpv癌基因调控，我们使用了作为肿瘤生长的细胞系。 在器官型上皮组织培养中能够概括整个HPV生命周期的组织。我们的数据显示 表皮生长因子受体信号转导和接触抑制对HPV癌基因的影响 表情。我们发现HPV癌基因的表达在转录水平下调的同时伴随着 当细胞变得越来越融合时，抑制EGFR信号。此外，表皮生长因子对血管紧张素转换酶刺激 融合细胞可以恢复E6和E7的表达，但这可以被EGFR、MEK或ERK的抑制剂所阻碍。 在这个提案中，我将定义调节E6/E7转录的EGFR的效应器，并将确定 表皮细胞相互作用影响EGFR信号转导病毒癌基因的机制 抄写。