Neurotensin in Fibrolamellar Liver Cancer
神经降压素在纤维板层肝癌中的作用
基本信息
- 批准号:9176932
- 负责人:
- 金额:$ 16.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-15 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAnchorage-Independent GrowthAppearanceArrestinsBAY 54-9085BehaviorBindingBiological AssayCREB1 geneCancer EtiologyCatalytic DomainCell Culture TechniquesCell LineCell ProliferationCessation of lifeChildChimeric ProteinsChromosomes, Human, Pair 19ChronicClinicalComplexCyclic AMPCyclic AMP-Dependent Protein KinasesDNA Sequence AlterationDataDevelopmentDiagnosisDiseaseEventExonsFibrolamellar Hepatocellular CarcinomaG Protein-Coupled Receptor SignalingG protein coupled receptor kinaseG-Protein-Coupled ReceptorsGRK1 geneGTP-Binding Protein alpha Subunits, GsGTP-Binding ProteinsGenesGenetic TranscriptionGenomicsGoalsGrowthHeat shock proteinsHepatocyteHistologicHoloenzymesHormonesHumanIncidenceIndividualLeftLightLinkLiverLiver CirrhosisLiver diseasesLiver neoplasmsMalignant NeoplasmsMalignant neoplasm of liverMediatingModelingMolecularMutationNeurosecretory SystemsNeurotensinOperative Surgical ProceduresOutcome StudyPRKACA genePathogenesisPathway interactionsPatientsPharmaceutical PreparationsPhenotypePhosphotransferasesPrimary Malignant Neoplasm of LiverPrimary carcinoma of the liver cellsProcessPromoter RegionsProprotein ConvertasesProteinsReportingRisk FactorsRoleSamplingSecondary toSignal TransductionSystemic TherapyTherapeuticTranscriptUp-RegulationVariantWorkabstractingadvanced diseaseage groupautocrinebasebeta-arrestincarcinogenesiscell typecombatdesensitizationeffective therapyfusion geneinsightliver cell proliferationliver injurymigrationmolecular phenotypemutantnovel therapeuticsoverexpressionprohormonereceptorresearch studytargeted cancer therapytargeted treatmenttumorigenesistumorigenicyoung adult
项目摘要
Project Summary/Abstract
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a form of primary liver cancer that afflicts
healthy children and young adults without underlying liver disease; approximately 90% of HCCs in
this age group are FL-HCCs. HCC as a whole is a remarkably diverse disease from a histologic and
molecular standpoint, and in the vast majority of adult cases arises in the setting of chronic liver injury
and cirrhosis. Conversely, FL-HCCs display consistent clinical behavior and have a homogeneous
histologic appearance, but there are no known risk factors. FL-HCC also differs from other subtypes
of HCC in that it arises in normal liver, and since these patients are healthy at baseline, they tend to
present with advanced disease, leaving no options for cure. Currently there are no effective non-
surgical therapies for patients with FL-HCC. Therefore we aim to develop targeted therapies for FL-
HCC patients through a detailed understanding of the molecular pathogenesis of this disease.
Recently, a putative causative mutation in FL-HCC was reported, and results in a chimeric
transcript consisting of the promoter region and first exon of a gene encoding a heat shock protein
(DNAJB1) fused to the majority of the sequence for the gene encoding the catalytic subunit of protein
kinase A (PRKACA). The mechanisms by which the resultant fusion protein drives carcinogenesis
remain unknown, though we have recently demonstrated increased PKA activity in FL-HCCs
compared to normal livers. The current proposal outlines experiments that will further investigate
drivers of excess PKA signaling in FL-HCC, with focus on the role of a neuroendocrine hormone in
this disease. Specifically, we will 1) evaluate the contribution of neurotensin to the development of
FL-HCC, 2) investigate how the DNAJB1-PRKACA fusion leads to neuroendocrine activation in these
cancers, and 3) define the oncologic effects of neurotensin/PKA signaling in the liver. In summary,
we propose to investigate the mechanisms by which the DNAJB1-PRKACA protein product
synergizes with neurotensin to drive carcinogenesis in FL-HCC, paving the way for the development
of targeted therapies for this cancer.
项目总结/文摘
项目成果
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