The Role of APE1/Ref-1 in Reflux-Induced Epithelial-Mesenchymal Transition in Benign Barrett's Metaplasia: A Novel Target for Preventing Recurrent Barrett's Esophagus After Radiofrequency Ablation
APE1/Ref-1 在良性 Barrett 化生中反流诱导的上皮间质转化中的作用:射频消融后预防 Barrett 食管复发的新靶点
基本信息
- 批准号:10337291
- 负责人:
- 金额:$ 36.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-13 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAbnormal CellAcidsAcuteBackBarrett EpitheliumBarrett EsophagusBenignBile fluidBurn injuryCell SurvivalCellsComplexComplicationDataDevelopmentDysplasiaEpithelialEpithelial CellsEsophageal AdenocarcinomaEsophagusEventExposure toFamily memberFrequenciesGastric JuiceGastroesophageal reflux diseaseGlandGoalsIn VitroInjuryIntestinal MetaplasiaIntestinesLamina PropriaLeadMalignant NeoplasmsMalignant neoplasm of esophagusMediatingMesenchymalMetaplasiaMolecularOxidation-ReductionOxidative StressPathway interactionsPatientsPerformancePharmaceutical PreparationsPlayPreventiveProceduresProcessProductionPublic HealthPublishingRadiofrequency Interstitial AblationReactive Oxygen SpeciesRecurrenceRefluxReportingResistanceRiskRisk FactorsRoleSignal TransductionSourceSquamous EpitheliumVascular Endothelial Growth Factorsbile saltscancer preventioncancer riskcell motilitycost effectiveexperimental studygene repressiongenetic corepressorin vivoinhibitorneoplasticnovelpremalignantpreventprogramspromoterrandomized trialtargeted treatmenttranscription factortreatment choicetumorwound healing
项目摘要
Project Summary
Barrett’s esophagus, the condition in which the normal squamous lining of the esophagus is replaced by a
metaplastic intestinal-type lining, is a risk factor for esophageal adenocarcinoma. This deadly cancer can be
prevented by radiofrequency ablation (RFA), an endoscopic procedure that burns away the cancer-prone
metaplastic lining. Presently, RFA is used only to eradicate Barrett’s esophagus that has precancerous
changes called dysplasia. After RFA, patients require regular endoscopic cancer surveillance because
Barrett’s metaplasia recurs frequently. Although RFA potentially could prevent cancer for the millions of
patients with non-dysplastic Barrett’s esophagus, RFA cannot be cost-effective for them unless it permanently
eradicates Barrett’s metaplasia. A condition called subsquamous intestinal metaplasia (SSIM) might underlie
the frequent recurrences of Barrett’s esophagus after RFA. In SSIM, Barrett’s cells are located under a layer of
normal esophageal squamous lining that shields them from destruction by RFA. Most Barrett’s patients have
SSIM, which could be the nidus for recurrent metaplasia after RFA. Our published data suggest that SSIM
develops when Barrett’s cells undergo a process called epithelial-mesenchymal transition (EMT), which is a
wound-healing event triggered by gastroesophageal reflux disease (GERD). EMT endows Barrett’s cells with
migratory abilities that enable them to move under the adjacent squamous lining. EMT also activates cell
survival pathways that could enable Barrett’s cells wounded by RFA to survive. Thus, EMT appears to underlie
the development of SSIM, and EMT might well underlie the high frequency of metaplasia recurrences after
RFA. In Barrett’s cells, we have reported that acid and bile (the damaging factors in gastric juice that refluxes
into the esophagus in GERD patients) induce oxidative stress that results in the accumulation of a molecule
called HIF-1α. We also published that acidic bile salts induce signaling through a molecular pathway that
causes Barrett’s cells to increase their production of ZEB1, a molecule that plays a key role in inducing the
EMT that triggers the cell motility leading to the development of SSIM. Our new experiments demonstrate that
acidic bile salts activate the function of a molecule called APE1/Ref-1 that is required for activation of HIF-1α.
We show that activated HIF-1α mediates increased production of the ZEB1 that induces EMT. Thus, we
hypothesize that GERD-induced APE1/Ref-1 function that activates HIF-1α is the pivotal event in initiating
EMT that enables Barrett’s cells to form SSIM and to survive RFA, and that these events might be prevented
by drugs that inhibit APE1/Ref-1. The aims of this study are to elucidate the mechanism(s) whereby APE1/Ref-
1 signaling and HIF-1α activation contribute to the induction of EMT, and to explore the role of the APE1/Ref-1-
HIF-1α signaling axis in EMT induced by exposure to acidic bile salts in Barrett’s esophagus. Our ultimate goal
is to determine how SSIM develops and how a targeted treatment might be used to prevent that development,
findings that could provide the means to eradicate Barrett’s esophagus and its cancer risk permanently.
项目总结
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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{{ truncateString('RHONDA F SOUZA', 18)}}的其他基金
The Role of APE1/Ref-1 in Reflux-Induced Epithelial-Mesenchymal Transition in Benign Barrett's Metaplasia: A Novel Target for Preventing Recurrent Barrett's Esophagus After Radiofrequency Ablation
APE1/Ref-1 在良性 Barrett 化生中反流诱导的上皮间质转化中的作用:射频消融后预防 Barrett 食管复发的新靶点
- 批准号:
10532359 - 财政年份:2020
- 资助金额:
$ 36.1万 - 项目类别:
Reflux-Induced Epithelial-Mesenchymal Transition in Benign Barrett's Esophagus
良性巴雷特食管反流诱导的上皮间质转化
- 批准号:
9148175 - 财政年份:2015
- 资助金额:
$ 36.1万 - 项目类别:
Reflux-Induced Epithelial-Mesenchymal Transition in Benign Barrett's Esophagus
良性巴雷特食管反流诱导的上皮间质转化
- 批准号:
8996772 - 财政年份:2015
- 资助金额:
$ 36.1万 - 项目类别:
Reflux-Induced Epithelial-Mesenchymal Transition in Benign Barrett's Esophagus
良性巴雷特食管反流诱导的上皮间质转化
- 批准号:
9750712 - 财政年份:2015
- 资助金额:
$ 36.1万 - 项目类别:
Role of Acid in the Development of Barrett's Esophagus
酸在巴雷特食管发育中的作用
- 批准号:
8011604 - 财政年份:2010
- 资助金额:
$ 36.1万 - 项目类别:
Role of IL-6/STAT3 Signaling in the Neoplastic Progression of Barrett's Esophagus
IL-6/STAT3 信号转导在 Barrett 食管肿瘤进展中的作用
- 批准号:
8246950 - 财政年份:2010
- 资助金额:
$ 36.1万 - 项目类别:
Role of IL-6/STAT3 Signaling in the Neoplastic Progression of Barrett's Esophagus
IL-6/STAT3 信号转导在 Barrett 食管肿瘤进展中的作用
- 批准号:
8445155 - 财政年份:2010
- 资助金额:
$ 36.1万 - 项目类别:
Role of IL-6/STAT3 Signaling in the Neoplastic Progression of Barrett's Esophagus
IL-6/STAT3 信号转导在 Barrett 食管肿瘤进展中的作用
- 批准号:
8045096 - 财政年份:2010
- 资助金额:
$ 36.1万 - 项目类别:
Role of IL-6/STAT3 Signaling in the Neoplastic Progression of Barrett's Esophagus
IL-6/STAT3 信号转导在 Barrett 食管肿瘤进展中的作用
- 批准号:
8696814 - 财政年份:2010
- 资助金额:
$ 36.1万 - 项目类别:
Basic and Clinical Studies on the Role of Bile Acids in Barrett's Esophagus
胆汁酸在巴雷特食管中作用的基础和临床研究
- 批准号:
8434197 - 财政年份:2009
- 资助金额:
$ 36.1万 - 项目类别:
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