Exploring the Role of DMBT1 Suppression in Invasion of Oral Cancer
探索 DMBT1 抑制在口腔癌侵袭中的作用
基本信息
- 批准号:10696941
- 负责人:
- 金额:$ 5.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AftercareBacteriaBacterial InfectionsBindingBiologicalBiological AssayCancer EtiologyCell LineCellsChemicalsDataDown-RegulationEnzyme-Linked Immunosorbent AssayEpithelial CellsEpitheliumFeedbackGeneticGenetic TranscriptionGoalsHumanImmuneIn VitroInflammatoryInterleukin-6InvadedLateralLesionMalignant Epithelial CellMalignant NeoplasmsMass Spectrum AnalysisMediatingMicrobeModelingMolecularMusOralOral healthPatientsPeriodontal DiseasesPorphyromonas gingivalisPredispositionProliferatingPromoter RegionsProtein SecretionProteinsProteomicsQuantitative Reverse Transcriptase PCRRecurrenceResearchRoleSalivaSalivary GlandsSignal PathwaySignal TransductionSquamous cell carcinomaTestingTransfectionTransforming Growth Factor betaTransforming Growth FactorsTumor Cell InvasionTumor Suppressor ProteinsValidationWestern BlottingWith lateralityactivating transcription factor 3antimicrobialcancer cellcell typechemical carcinogenesiscytokinedysbiosisenhancing factorepidemiology studyglycoprotein 340improvedin vitro Assayin vivo Modelinhibitorkeratinocytemalignant mouth neoplasmmicrobiomemigrationmouth squamous cell carcinomaneoplastic cellnew therapeutic targetoral microbiomeoral pathogenpathogenpharmacologicpreventrecruitrelease factorresponsetherapeutic targettranscription factortumortumor progression
项目摘要
PROJECT SUMMARY/ABSTRACT
Squamous cell carcinoma (SCC), the most common oral cancer, notoriously recurs, leading to poor survival.
Invasion of cancer cells is essential for recurrence and progression, emphasizing the importance of investigating
mechanisms of invasion in order to improve patient survival. We recently identified a mechanism in which SCC
co-opts adjacent non-cancerous epithelium, referred to as cancer-associated keratinocytes (CAKs), to enhance
lateral invasion, which was associated with recurrence. Deleted in malignant brain tumors 1 (DMBT1), a tumor
suppressor, is downregulated in SCC to promote lateral invasion and formation of satellite lesions. In a feedback
loop, SCC-secreted transforming growth factor-beta (TGF) suppresses DMBT1 in CAKs; this causes CAKs to
release cytokines that enhance invasion of tumor cells away from the tumor bulk. The objective of the proposed
study is to understand how TGF suppresses DMBT1 in CAKs and why it does so. Interestingly, DMBT1 is also
an anti-microbial protein; preliminary data show that downregulation of DMBT1 in CAKs increases susceptibility
to Porphyromonas gingivalis, a keystone pathogen in periodontal disease. There is a strong correlation between
SCC and dysbiosis in the oral microbiome. Multiple studies have shown that P. gingivalis enhances SCC
invasion, but none have examined the ability of P. gingivalis to enhance SCC invasion via CAKs. Normal
keratinocytes infected with P. gingivalis secrete pro-inflammatory cytokines. The overall hypothesis is that
SCC-mediated suppression of DMBT1 in CAKs via TGF facilitates bacterial entry into CAKs, thereby
enhancing release of cytokines that promote invasion of SCC. To test this hypothesis, we propose two aims:
Aim #1: Characterize the molecular mechanism by which TGF suppresses DMBT1 in CAKs; and Aim #2:
Investigate the impact of DMBT1 suppression in CAKs on bacterial entry, release of pro-invasive cytokines, and
SCC invasion. To understand the mechanism of DMBT1 suppression in CAKs, we will use in genetic and
pharmacological approaches in cell lines. To understand the significance of DMBT1 suppression in CAKs on
SCC invasion, we will use high-throughput proteomics to investigate the secretome of CAKs, and genetic and
pharmacologic approaches to establish the role of these cytokines in invasion using in in vitro and in vivo models,
including Dmbt1-/- mice. Overall, this project will investigate the mechanism by which SCC co-opts CAKs to
promote the release of cytokines that enhance tumor invasion; this could provide therapeutic targets to prevent
SCC recurrence and improve survival.
项目总结/摘要
鳞状细胞癌(SCC)是最常见的口腔癌,众所周知会复发,导致生存率低下。
癌细胞的侵袭对于复发和进展至关重要,强调了研究的重要性。
以提高患者的生存率。我们最近发现了一种机制,
选择邻近的非癌上皮,称为癌症相关角质形成细胞(CAK),以增强
外侧侵犯,这与复发有关。恶性脑肿瘤1(DMBT 1),
在SCC中下调,以促进侧向侵袭和卫星病变的形成。以反馈
环,SCC分泌的转化生长因子β(TGF β)抑制CAKs中的DMBT 1;这导致CAKs
释放增强肿瘤细胞远离肿瘤块的侵袭的细胞因子。建议的目标
这项研究的目的是了解TGF β 1如何抑制CAKs中的DMBT 1以及为什么会这样。有趣的是,DMBT 1也是
一种抗微生物蛋白;初步数据显示CAKs中DMBT 1的下调增加了易感性
牙龈卟啉单胞菌,牙周病的关键病原体。之间存在很强的相关性
口腔微生物群中的SCC和生态失调。多项研究表明,牙龈卟啉单胞菌可增强SCC
但是没有人检测牙龈卟啉单胞菌通过CAK增强SCC侵袭的能力。正常
感染牙龈卟啉单胞菌的角质形成细胞分泌促炎细胞因子。总的假设是,
SCC介导的通过TGF β 1抑制CAKs中的DMBT 1促进细菌进入CAKs,从而
促进细胞因子的释放,促进SCC的侵袭。为了验证这一假设,我们提出了两个目标:
目的#1:表征TGF β 1抑制CAK中DMBT 1的分子机制;以及目的#2:
研究CAK中DMBT 1抑制对细菌进入、促侵袭细胞因子释放和
SCC入侵。为了了解CAKs中DMBT 1抑制的机制,我们将使用遗传和
细胞系的药理学方法。为了了解CAKs中DMBT 1抑制的意义,
SCC的侵袭,我们将使用高通量蛋白质组学研究CAKs的分泌组,以及基因和
使用体外和体内模型建立这些细胞因子在侵袭中的作用的药理学方法,
包括Dmbt 1-/-小鼠。总的来说,本项目将调查SCC增选CAK的机制,
促进细胞因子的释放,增强肿瘤侵袭;这可以提供治疗靶点,以防止
SCC复发,提高生存率。
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)
专利数量(0)
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Erika Bunnine Danella其他文献
Erika Bunnine Danella的其他文献
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{{ truncateString('Erika Bunnine Danella', 18)}}的其他基金
Exploring the Role of DMBT1 Suppression in Invasion of Oral Cancer
探索 DMBT1 抑制在口腔癌侵袭中的作用
- 批准号:
10462188 - 财政年份:2022
- 资助金额:
$ 5.35万 - 项目类别:
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