ESCRT-dependent novel regulatory mechanism of EMT and tumorigenesis in oral cancer

口腔癌 EMT 和肿瘤发生的 ESCRT 依赖性新调控机制

• 批准号: 10391608
• 负责人: Radhika Gudi
• 金额: $ 37.75万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391608
• 关键词: ATP phosphohydrolase; Binding; Biogenesis; Biological; Carrier Proteins; Cell Line; Cells; Centrioles; Centrosome; Chemoresistance; Clinical; Complex; Continuous Positive Airway Pressure; Data; Defect; Development; Down-Regulation; Drug Targeting; Endocytic Vesicle; Endocytosis; Endosomes; Epidermal Growth Factor Receptor; Epithelial; Event; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Generations; Genetic Models; Goals; Growth; Homeostasis; Knock-in Mouse; Knock-out; Knockout Mice; Knowledge; Lead; Ligands; Link; Lysosomes; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Manuscripts; Mediating; Mediator of activation protein; Mesenchymal; Microtubules; Molecular; Multivesicular Body; Mutagenesis; Neoplasm Metastasis; Nitroquinolines; Oral; Oxides; Pathway interactions; Patients; Phenotype; Physiological; Predisposition; Prevention; Preventive; Property; Protein Overexpression; Proteins; Receptor Down-Regulation; Receptor Signaling; Recurrence; Regulation; Resistance; Role; Route; Signal Transduction; Solid; Sorting - Cell Movement; Structure; Surface; Testing; Time; Tissues; Translating; Tubulin; Tubulin Interaction; Tumor Suppressor Proteins; Tumorigenicity; Unfavorable Clinical Outcome; Vesicle; base; cancer cell; cancer stem cell; epithelial to mesenchymal transition; loss of function; malignant mouth neoplasm; mouth squamous cell carcinoma; novel; oral carcinogenesis; oral tumorigenesis; overexpression; prevent; protein function; receptor; receptor expression; recruit; therapeutic target; trafficking; tumor; tumor progression; tumorigenesis; tumorigenic; vesicle transport

PROJECT DESCRIPTION/ABSTRACT Epidermal growth factor receptor (EGFR) is overexpressed in majority of tumors including oral squamous cell carcinoma (OSCC). The over-expressed/-activated EGFR contributes to epithelial-mesenchymal transition (EMT) and tumor progression by contributing to tumor metastasis and chemo-resistance. Hence, EGFR has become one of the major therapeutic targets for OSCC. Endocytosis is a key biological pathway for internalization of ligand activated EGFR, following which it gets routed for lysosomal degradation by the endosomal sorting complex for recruitment and transport (ESCRT) machinery. ESCRT is a key mediator of endocytic vesicle trafficking (EVT). While vesicle trafficking defects result in the poor downregulation of activated EGFR, persistent surface and cellular EGFR expression and signaling is subsequently linked to the development of cancer. Surprisingly, the molecular events/mechanisms that regulate ESCRT pathway which is critical for maintaining EGFR homeostasis and preventing EMT and tumorigenesis are largely unknown. Here, based on solid preliminary data, we propose to investigate a previously unknown mechanism that regulates ESCRT dependent EVT, EGFR levels and signaling, EMT, and OSCC growth. We found that 1) depletion of CPAP caused the prolonged expression of EGFR and an EMT-like phenotype in oral cancer cells; 2) while depletion of CPAP enhanced the tumorigenicity of an OSCC cell line, overexpression of CPAP in this cell line suppressed its tumor inducing potential; 3) overexpression of CPAP caused the de novo generation of EGFR- positive multivesicular bodies, whose biogenesis requires ESCRT and are essential intermediates that route EGFR to lysosomes for degradation and termination of its signaling; and 4) the absence of CPAP resulted in diminished cellular levels of VPS4 protein, an essential ESCRT associated ATPase that facilitates pinching off of endocytic vesicles. These collective observations suggest that CPAP induced positive regulation of ESCRT pathway and EVT maintains EGFR homeostasis, resulting in prevention of EMT and tumorigenesis in OSCC. This novel hypothesis will be tested systematically under two specific aims. The primary goals of aim 1 will be to define the molecular mechanisms by which CPAP positively regulates EVT and EGFR homeostasis in OSCC. This will be done by using OSCC and normal oral cells with gain-and-loss-of-function of CPAP as well as by studying CPAP-ESCRT interaction in the context of EGFR homeostasis. We will then, under aim 2, determine the role of CPAP in preventing EMT and oral tumorigenesis. This will be achieved by characterizing CPAP gain- and-loss-of-function in OSCC cell lines for EMT features, and growth and tumorigenic properties, and by studying the oral cancer susceptibility using a conditional CPAP-knockout mice. Overall, this study will delineate a novel ESCRT dependent mechanism that prevents OSCC.

项目描述/文摘