Modulation of junctional signaling by BVES in colorectal carcinoma
BVES 对结直肠癌中连接信号的调节
基本信息
- 批准号:8698302
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-07-01 至 2016-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdenomatous PolypsAdherens JunctionAdhesionsAdhesivesAffectAnchorage-Independent GrowthAttenuatedBCAR3 geneBindingBiological AssayBiological MarkersBiologyBlood VesselsBreastCDK4 geneCancer ControlCancer EtiologyCancer cell lineCell Adhesion MoleculesCell Culture TechniquesCell CycleCell LineCell ProliferationCell membraneCell-Cell AdhesionCellsClinicalColonColon CarcinomaColorectal CancerComplexCpG IslandsCyclin D1CytokeratinDataDecitabineDeoxycytidineDevelopmentDiagnosisDiagnosticDiseaseDominant-Negative MutationDysmyelopoietic SyndromesE-CadherinE-Cadherin Staining MethodEpigenetic ProcessEpithelialEpithelial CellsEventFDA approvedFunctional disorderGene ActivationGeneticGrowthHealth PersonnelHealthcare SystemsHumanHybridsHypermethylationIncidenceInflammatoryLarge Intestine CarcinomaLinkMalignant - descriptorMalignant Epithelial CellMalignant NeoplasmsMalignant neoplasm of ovaryMapsMechanicsMediatingMembraneMesenchymalMethylationModelingMolecularMorphologyMusMyosin ATPaseNeoplasm MetastasisNuclearNude MiceOvarianPathologyPathway interactionsPhenotypePlayProcessProteinsProto-OncogenesRHOA geneRegulator GenesRegulatory PathwayReporterRepressionResistanceRoleSW620SamplingSignal PathwaySignal TransductionSmall Interfering RNAStagingStructureSurveysTestingTight JunctionsTranscriptional ActivationTreatment EfficacyTumor BiologyTumor Suppressor ProteinsUnited StatesUnited States Department of Veterans AffairsVeteransVimentinWNT Signaling PathwayWound HealingXenograft procedureYeastsattenuationbaseblood vessel restorationburden of illnesscancer cellcancer diagnosiscarcinogenesiscell motilityclaudin 3colorectal cancer preventioncorneal epitheliumdesignin vivoinsightknock-downmalignant phenotypemalignant stomach neoplasmmigrationmonolayermortalitynew therapeutic targetnovelnovel diagnosticsoverexpressionprogramspromoterrhoscreeningsplenic capsuletherapeutic targettumortumor growthtumorigenesistumorigenic
项目摘要
DESCRIPTION (provided by applicant):
Colorectal cancer (CRC) has a US incidence rate of almost 150,000 cases encompassing over 10% of new cancer diagnoses. In 2006 Within the Veterans Administration Healthcare System there were 4500 new cases and of those 650 were at advanced stage with very limited treatment options. Understanding the basic biology of underlying malignant transformation is critical in identifying new therapeutic targets and implementable strategies. Epithelial junctional pathology is common in malignancy. Decreased expression or mislocalization of E-cadherin, an adherens junction protein, has long been implicated in CRC. Claudin -3, -4, and -7, all transmembrane tight junction proteins, are overexpressed in ovarian, CRC, and gastric cancers and knock-down of claudin-3 and -4 in ovarian cancer cell lines leads to reduced invasiveness. Thus, both tight and adherens junctional dysfunction is implicated in CRC. BVES is a tight junction associated protein which when suppressed induces mesenchymal transformation in human corneal epithelial cells. Because mesenchymal transformation occurs in late stage CRC, facilitating metastasis, we postulated that BVES may be altered in CRC. We found decreased expression of BVES in CRC. BVES was underexpressed in adenomatous polyps indicating that loss of expression is an early event, likely implicating BVES in regulating additional pro- tumorigenic programs in addition to potentially contributing to metastasis. We determined the mechanism of underexpression was via transcriptional silencing via promoter hypermethylation, occurring in a large fraction of clinical samples, and virtually all CRC cell lines surveyed. We tested the functional relevance of BVES loss by restoring its expression in LIM2405 cells. These cells are weakly adherent, highly proliferative, migratory, and invasive. BVES strikingly reversed all of these phenotypes causing "epithealization" of the line with conversion to epithelial morphology and increased expression of cytokeratin and reciprocal loss of vimentin. These phenotypic changes were associated with increased E-cadherin expression with a shift in ¿-catenin distribution to the cell membrane with associated decreased WNT reporter activity, implicating BVES in regulating a known cancer-signaling pathway. Additionally, in investigating the mesenchymal phenotype, we observed increased GEF-H1, BVES, Zo-1 membrane accumulation with decreased RHOA activity; indicating BVES could regulate Rho signaling. Furthermore, BVES expression in LIM2405 cells attenuated tumor growth as nude mouse xenografts and blocked SW620 metastasis. Collectively, this data suggests that BVES functions as a tumor suppressor in epithelial malignancy, thus BVES may represent a new diagnostic marker and/or therapeutic target in cancer. Much remains to be known about BVES function in epithelial malignancy. In this proposal we structure three specific aims designed to understand the role of BVES in tumor biology. First we will use murine genetic approaches to test for BVES cooperation with APC in promoting tumorigenesis and to test for a role for BVES in inflammatory carcinogenesis. We also propose mechanistic structure function studies to map BVES functional domains contributing to BVES dependent phenotypes. We have performed a yeast 2-hybrid screen and identified a panel of BVES interacting proteins. We propose characterizing the interaction between BVES and BCAR3 a breast protooncogene with GEF activity known to regulate RHO dependent processes. Lastly, we will determine if restoration of BVES expression using epigenetic modifying agents reverses the malignant phenotype of CRC cells. This could provide support for using BVES methylation as a diagnostic marker to guide therapy. Through these studies we will gain fundamental insight into how loss of BVES contributes to malignant progression, potentially providing evidence that supports developing BVES as a therapeutic target or diagnostic marker in colorectal carcinoma and addressing Provocative Question #20 from the NCI "...can biomarkers or signatures be identified that can serve as predictors or surrogates of therapeutic efficacy?".
描述(由申请人提供):
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Christopher S. Williams其他文献
P143 EPITHELIAL-DERIVED SELENOPROTEIN P PROTECTS FROM COLITIS-ASSOCIATED CARCINOGENESIS
P143 上皮来源的硒蛋白 P 可预防结肠炎相关的癌变
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2020 - 期刊:
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Sarah P. Short;V. K. Reddy;Jared R. Hendren;Y. Haberman;J. Pilat;Benjamin J. Marsh;M. Washington;J. Hyams;T. Denson;M. Rosen;Christopher S. Williams - 通讯作者:
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Mo1956 MAPPING IMMUNOGENIC EPITOPES OF ADALIMUMAB USING VALIMABSEQ
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10.1016/s0016-5085(23)03183-9 - 发表时间:
2023-05-01 - 期刊:
- 影响因子:
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Justin Jacobse;Lauren M. Walker;Clinton Holt;Jing Li;Jennifer M. Pilat;Dawn Beaulieu;Sara N. Horst;Robin L. Dalal;Baldeep S. Pabla;Elizabeth A. Scoville;David A. Schwartz;Christopher S. Williams;Lori A. Coburn;Ivelin Georgiev;Jeremy A. Goettel - 通讯作者:
Jeremy A. Goettel
Su1116 – Eosinophils are Present in Human and Mouse Escc Tumors and May Be Protective in Tumorigenesis
- DOI:
10.1016/s0016-5085(19)38148-x - 发表时间:
2019-05-01 - 期刊:
- 影响因子:
- 作者:
Yash A. Choksi;Jasmine Chaparro;Kay Washington;Anil K. Rustgi;Christopher S. Williams - 通讯作者:
Christopher S. Williams
Su1785 - Breast Cancer Anti-Estrogen Resistance 3 (BCAR3) in Colorectal Cancer Migration and Intestinal Homeostasis
- DOI:
10.1016/s0016-5085(17)32020-6 - 发表时间:
2017-04-01 - 期刊:
- 影响因子:
- 作者:
Joshua J. Thompson;Kan He;Sarah P. Short;Xi Chen;Cody Keating;Yash A. Choksi;Christopher S. Williams - 通讯作者:
Christopher S. Williams
130 MTGR1 Is Required for Gsi-Induced Paneth Cell Differentiation
- DOI:
10.1016/s0016-5085(13)60110-9 - 发表时间:
2013-05-01 - 期刊:
- 影响因子:
- 作者:
Bobak Parang;Vishruth K. Reddy;Daniel Rosenblatt;Amanda Williams;Aubrey Hunt;Frank Revetta;Yuan-hung Lo;Kay Washington;Michael Engel;Scott W Hiebert;Noah F Shroyer;Christopher S. Williams - 通讯作者:
Christopher S. Williams
Christopher S. Williams的其他文献
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{{ truncateString('Christopher S. Williams', 18)}}的其他基金
Modulation of junctional signaling by BVES in colorectal carcinoma
BVES 对结直肠癌中连接信号的调节
- 批准号:
8510388 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Modulation of Junctional Signaling by BVES in Colorectal Carcinoma
BVES 对结直肠癌中连接信号的调节
- 批准号:
10620135 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Modulation of junctional signaling by BVES in colorectal carcinoma
BVES 对结直肠癌中连接信号的调节
- 批准号:
8332389 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Modulation of Junctional Signaling by BVES in Colorectal Carcinoma
BVES 对结直肠癌中连接信号的调节
- 批准号:
10392341 - 财政年份:2012
- 资助金额:
-- - 项目类别:
The role of MTGR1 in intestinal biology and inflammation
MTGR1 在肠道生物学和炎症中的作用
- 批准号:
8088182 - 财政年份:2008
- 资助金额:
-- - 项目类别:
The role of MTGR1 in intestinal biology and inflammation
MTGR1 在肠道生物学和炎症中的作用
- 批准号:
7362123 - 财政年份:2008
- 资助金额:
-- - 项目类别:
The role of MTGR1 in intestinal biology and inflammation
MTGR1 在肠道生物学和炎症中的作用
- 批准号:
7903416 - 财政年份:2008
- 资助金额:
-- - 项目类别:
The role of MTGR1 in intestinal biology and inflammation
MTGR1 在肠道生物学和炎症中的作用
- 批准号:
7625939 - 财政年份:2008
- 资助金额:
-- - 项目类别:
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