ESCRT-dependent novel regulatory mechanism of EMT and tumorigenesis in oral cancer
ESCRT-dependent novel regulatory mechanism of EMT and tumorigenesis in oral cancer
批准号:
10391608
负责人:
Radhika Gudi
金额:
$37.75万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-01 至 2027-05-31
关键词:
ATP phosphohydrolaseBindingBiogenesisBiologicalCarrier ProteinsCell LineCellsCentriolesCentrosomeChemoresistanceClinicalComplexContinuous Positive Airway PressureDataDefectDevelopmentDown-RegulationDrug TargetingEndocytic VesicleEndocytosisEndosomesEpidermal Growth Factor ReceptorEpithelialEventExploratory/Developmental Grant for Diagnostic Cancer ImagingGenerationsGenetic ModelsGoalsGrowthHomeostasisKnock-in MouseKnock-outKnockout MiceKnowledgeLeadLigandsLinkLysosomesMalignant - descriptorMalignant Epithelial CellMalignant NeoplasmsManuscriptsMediatingMediator of activation proteinMesenchymalMicrotubulesMolecularMultivesicular BodyMutagenesisNeoplasm MetastasisNitroquinolinesOralOxidesPathway interactionsPatientsPhenotypePhysiologicalPredispositionPreventionPreventivePropertyProtein OverexpressionProteinsReceptor Down-RegulationReceptor SignalingRecurrenceRegulationResistanceRoleRouteSignal TransductionSolidSorting - Cell MovementStructureSurfaceTestingTimeTissuesTranslatingTubulinTubulin InteractionTumor Suppressor ProteinsTumorigenicityUnfavorable Clinical OutcomeVesiclebasecancer cellcancer stem cellepithelial to mesenchymal transitionloss of functionmalignant mouth neoplasmmouth squamous cell carcinomanoveloral carcinogenesisoral tumorigenesisoverexpressionpreventprotein functionreceptorreceptor expressionrecruittherapeutic targettraffickingtumortumor progressiontumorigenesistumorigenicvesicle transport
中文摘要
项目描述/文摘
英文摘要
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.
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A novel ESCRT-associated regulatory mechanism of EMT in oral cancer
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批准号:9333643
-
项目类别:
-
资助金额:$22.43万
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财政年份:2017
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负责人:Radhika Gudi
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依托单位:
国内基金
海外基金
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