Targeted inhibition of eIF5Ahpu suppresses tumor growth and M2-like TAM polarization in oral cancer
靶向抑制 eIF5Ahpu 可抑制口腔癌中的肿瘤生长和 M2 样 TAM 极化
基本信息
- 批准号:10441837
- 负责人:
- 金额:$ 46.93万
- 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:2022-03-01 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAmino AcidsAttenuatedBMI1 geneBiological ProcessCell ProliferationCell physiologyCharacteristicsData SetDevelopmentDiagnosisDown-RegulationES01EnzymesEpithelialGeneticGenetic TranscriptionGrowthHead and Neck CancerHead and Neck Squamous Cell CarcinomaHumanImmuneImmunocompetentImmunosuppressionIn VitroInfiltrationLightLysineMalignant Epithelial CellMalignant NeoplasmsMediatingMesenchymalMetabolismMixed Function OxygenasesModelingMolecularMorbidity - disease rateMusNOTCH1 geneNormal tissue morphologyNude MiceODC1 geneOncogenesOrnithine DecarboxylasePatientsPharmacologyPhenotypePlayPolyaminesPost-Translational Protein ProcessingPreventionPrognosisPropertyProtein IsoformsProteinsRNA-Binding ProteinsRecurrenceRoleSchemeSignal PathwaySignal TransductionSpermidineSpermidine SynthaseStromal CellsSurvival RateT-Cell ActivationTWIST1 geneTestingThe Cancer Genome AtlasTherapeutic EffectTongue Squamous Cell CarcinomaTranslationsTumor-associated macrophagesUp-RegulationWestern Blottinganalogbasecancer cellcancer preventioncancer stem cellcancer typechemotherapycohortdensitydeoxyhypusine monooxygenasedeoxyhypusine synthasegenetic approachhypusinein vivoirradiationmRNA Expressionmacrophagemalignant mouth neoplasmmortalitymouth squamous cell carcinomanew therapeutic targetnovelnovel therapeuticsoverexpressionparacrinepolyamine oxidaseprotein expressionself-renewaltumortumor growthtumor microenvironmenttumor progressiontumor-immune system interactions
项目摘要
PROJECT SUMMARY
Oral squamous cell carcinoma (OSCC) is the most common type of head & neck cancer and the 10th most
frequent human malignancy worldwide. Over the last several decades, the overall survival rate of OSCC patients
has stagnated between 40~55% despite some progress in diagnosis and therapy. The invasive growth or
progression of OSCC relies on the aggressiveness of cancer cells and their unique microenvironment, whereby
cancer stem cells (CSCs) and infiltrated tumor associated macrophages (TAMs) play pivotal roles. Previous
studies have demonstrated that polyamines (PA) are commonly elevated in tumor microenvironment (TME) and
have long been proven to be necessary for transformation and progression of various types of cancers. eIF5A2,
an isoform of a highly conserved translational factor, is overexpressed in many types of cancer. Remarkably,
spermidine-mediated eIF5A hypusination (eIF5Ahpu) that is implemented by two highly specialized enzymes,
deoxyhypusine synthase (DHS/DHPS) and deoxyhypusine hydroxylase (DOHH), appears to be essential to most,
if not all, of eIF5A’s biological functions, including its important role in regulating cancer cell proliferation,
epithelial-mesenchymal transition (EMT), and CSC properties as well as immune cell functions, thus rationally
emerging as a potential target for both therapy and prevention of cancer. Our analysis of TCGA dataset indicated
an overall upregulation in the mRNA expression of eIF5A2 and several key enzymes involved in PA metabolism
in HNSCC, which was confirmed by Western blot and IHC studies. Our studies showed that blocking
DHPS/eIF5Ahpu remarkably inhibited proliferation and CSC properties of OSCC cells, which correlated a
downregulation of TWIST1-BMI1 expression and NOTCH1/HES1 signaling. Meanwhile, we found that blocking
DHPS/eIF5Ahpu robustly inhibited OSCC-induced polarization of M2-like TAMs and reversed the
immunosuppressive effects conferred by OSCC-induced TAMs on T cell activation in vitro. More Importantly,
we found that blocking DHPS/eIF5Ahpu dramatically retarded tumor growth and infiltration/polarization of M2-like
TAM in an orthotopic syngeneic mouse tongue SCC model. Based on these compelling preliminary studies, we
hypothesize that eIF5Ahpu might play a critical role in OSCC growth and progression due to its dual functions in
regulating proliferation/CSC properties of OSCC cells and OSCC-induced M2-like TAM polarization. To test our
hypothesis, we propose three specific aims: 1) Elucidate mechanism by which eIF5Ahpu regulates proliferation
and CSC properties in OSCC; 2) Determine whether eIF5Ahpu plays a critical role in OSCC-induced polarization
of M2-like TAMs; 3) Target eIF5Ahpu to suppress tumor growth and immunosuppressive TAMs in OSCC in vivo.
New findings from this application might not only shed light on elucidating the function of eIF5Ahpu activation in
development and progression of OSCC, but also hold promises for identifying novel therapeutic targets for
treatment and prevention of OSCC.
项目总结
项目成果
期刊论文数量(0)
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{{ truncateString('Anh D Le', 18)}}的其他基金
Targeted inhibition of eIF5Ahpu suppresses tumor growth and M2-like TAM polarization in oral cancer
靶向抑制 eIF5Ahpu 可抑制口腔癌中的肿瘤生长和 M2 样 TAM 极化
- 批准号:
10573290 - 财政年份:2022
- 资助金额:
$ 46.93万 - 项目类别:
Therapeutic Potential of Gingival mesenchymal Stem Cell-derived Extracellular Vesicles Enriched with MFG-E8 in Peripheral Nerve Regeneration
富含 MFG-E8 的牙龈间充质干细胞来源的细胞外囊泡在周围神经再生中的治疗潜力
- 批准号:
10180941 - 财政年份:2020
- 资助金额:
$ 46.93万 - 项目类别:
Therapeutic Potential of Gingival mesenchymal Stem Cell-derived Extracellular Vesicles Enriched with MFG-E8 in Peripheral Nerve Regeneration
富含 MFG-E8 的牙龈间充质干细胞来源的细胞外囊泡在周围神经再生中的治疗潜力
- 批准号:
10042927 - 财政年份:2020
- 资助金额:
$ 46.93万 - 项目类别:
GINGIVA DERIVED MSCS: ROLE IN IMMUNOMODULATION AND TISSUE REGENERATION
牙龈源性间充质干细胞:在免疫调节和组织再生中的作用
- 批准号:
7728606 - 财政年份:2009
- 资助金额:
$ 46.93万 - 项目类别:
GINGIVA DERIVED MSCS: ROLE IN IMMUNOMODULATION AND TISSUE REGENERATION
牙龈源性间充质干细胞:在免疫调节和组织再生中的作用
- 批准号:
8271275 - 财政年份:2009
- 资助金额:
$ 46.93万 - 项目类别:
GINGIVA DERIVED MSCS: ROLE IN IMMUNOMODULATION AND TISSUE REGENERATION
牙龈源性间充质干细胞:在免疫调节和组织再生中的作用
- 批准号:
7851425 - 财政年份:2009
- 资助金额:
$ 46.93万 - 项目类别:
GINGIVA DERIVED MSCS: ROLE IN IMMUNOMODULATION AND TISSUE REGENERATION
牙龈源性间充质干细胞:在免疫调节和组织再生中的作用
- 批准号:
8070529 - 财政年份:2009
- 资助金额:
$ 46.93万 - 项目类别:
GINGIVA DERIVED MSCS: ROLE IN IMMUNOMODULATION AND TISSUE REGENERATION
牙龈源性间充质干细胞:在免疫调节和组织再生中的作用
- 批准号:
8600475 - 财政年份:2009
- 资助金额:
$ 46.93万 - 项目类别:
GINGIVA DERIVED MSCS: ROLE IN IMMUNOMODULATION AND TISSUE REGENERATION
牙龈源性间充质干细胞:在免疫调节和组织再生中的作用
- 批准号:
8466720 - 财政年份:2009
- 资助金额:
$ 46.93万 - 项目类别:
BOWMAN-BIRK INHIBITOR CONCENTRATE & ORAL LEUKOPLAKIA: PHASE IIB TRIAL (UNIVER
BOWMAN-BIRK 抑制剂浓缩液
- 批准号:
7716696 - 财政年份:2008
- 资助金额:
$ 46.93万 - 项目类别:
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