Consequences and mechanism of aberrant splicing in African American prostate cancer disparities
非裔美国人前列腺癌差异中异常剪接的后果和机制
基本信息
- 批准号:10116165
- 负责人:
- 金额:$ 35.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-03-01 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAddressAfrican AmericanAlternative SplicingAmericanAutomobile DrivingBackBindingBiological AssayCRISPR/Cas technologyCatalytic DomainCell LineCell ProliferationCell-Free SystemCellsCharacteristicsChemoresistanceClipCodeComplementComplementary DNAComputer AnalysisDNA MethylationDNA cassetteDataDevelopmentDiseaseElementsEnhancersEuropeanEventExhibitsExonsFGFR3 geneFibroblast Growth Factor ReceptorsFutureGenerationsGenesHealthHistonesHumanIn VitroIncidenceIndividualIntegrinsKnock-outMalignant NeoplasmsMalignant neoplasm of prostateMediatingMessenger RNAMicroRNAsMolecularMusNatureNeoplasm MetastasisOncogenicPatientsPatternPhenotypePhosphatidylinositol 4,5-DiphosphatePhosphotransferasesPopulationProductionPrognosisProtein IsoformsProteinsPublishingRNA SequencesRNA SplicingRaceReceptor Protein-Tyrosine KinasesRecombinantsRegulationRegulator GenesResistanceRoleSRSF2 geneSignal PathwaySignal TransductionSiteSpecimenSystemTechniquesTechnologyTestingTranscriptional ActivationTransplantationTumor Suppressor GenesUbiquitinationUp-RegulationVariantVascular Endothelial Growth FactorsXenograft ModelXenograft procedurecancer health disparitycancer survivalcellular imagingdifferential expressiondruggable targetepithelial to mesenchymal transitionexon skippingexperimental studyfibroblast growth factor-14gain of functiongenetically modified cellshealth disparityhigh riskimaging approachin vitro Assayknock-downmimeticsmortalitymouse modeloverexpressionprostate cancer cellprostate cancer cell lineprostate cancer riskracial disparitysmall hairpin RNAsmall moleculesmall molecule inhibitorstable cell linestatisticssurvival outcometargeted treatmenttranscription factortumortumor growth
项目摘要
Summary
There are striking population (race) disparities in prostate cancer (PCa) risk and survival outcome borne out of
current health statistics. This is particularly evident between African American (AA) patients and their European
American (EA) counterparts, where AAs exhibit a 1.5 to 2 fold higher risk of PCa incidence and mortality. We
demonstrate that differential alternative RNA splicing takes place for oncogenes and tumor suppressor genes
in PCa specimens of AA compared to EA patients. The differential splicing events result in the enrichment and
in many instances generation of AA-specific splice variants not observed in EA cancers. We have cloned the
AA and EA splice variant cDNAs for both phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta
(PIK3CD) and fibroblast growth factor receptor 3 (FGFR3), and ectopically introduced the clones individually
into PCa cell lines. Compared to the EA variant-expressing lines, the AA variant-expressing lines are more
oncogenic in in vitro cell proliferation and invasion assays, and exhibit greater tumor growth/metastasis and
resistance to small molecule targeted therapy in xenograft mouse models. These findings may explain, in part,
the observed cancer health disparities in the AA population relative to other racial groups. The mechanism
responsible for the formation of AA-specific or -enriched mRNA splice variants are hypothesized to be due to
the dysregulated expression of 6 key splicing factor s in AA PCa specimens. We refer to this dysregulation and
associated production of AA-specific splice variants as an “AA splicing factor code in PCa disparities.”
Notwithstanding these developments, a number of questions remain unresolved. First, what is the
mechanism(s) of dysregulated expression of the 6 splicing factors? Second, can the production of AA-specific
splice variants via exon skipping be directly attributed to the 6 dysregulated splicing factors? Lastly, how do the
encoded proteins of the AA-specific short variants of PIK3CD and FGFR3 mediate a more oncogenic
phenotype in PCa cells? The objectives of this application are to address these questions, and to provide a
mechanistic framework of population-related differences in alternative RNA splicing, which is anticipated to
facilitate future identification of druggable targets (e.g. splicing factors and/or resulting splice variant proteins)
of AA tumor phenotype and disparities.
总结
前列腺癌(PCa)风险和生存结局存在显著的人群(种族)差异,
目前的卫生统计数据。这在非洲裔美国人(AA)患者和他们的欧洲人之间尤其明显。
美国(EA)同行,其中AA表现出PCa发病率和死亡率高1.5至2倍的风险。我们
表明癌基因和肿瘤抑制基因发生差异性RNA剪接,
在AA的PCa标本与EA患者相比。差异剪接事件导致富集,
在许多情况下,在EA癌中未观察到AA特异性剪接变体的产生。我们克隆了
磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基δ的AA和EA剪接变体cDNA
(PIK 3CD)和成纤维细胞生长因子受体3(FGFR 3),并且异位地分别引入克隆
转化为前列腺癌细胞系。与EA突变体表达系相比,AA突变体表达系的遗传多样性更高,
在体外细胞增殖和侵袭测定中致癌,并表现出更大的肿瘤生长/转移,
在异种移植小鼠模型中对小分子靶向疗法的抗性。这些发现可以部分解释,
观察到AA人群相对于其他种族群体的癌症健康差异。机制
负责形成AA特异性或富集的mRNA剪接变异体的假设是由于
AA PCa标本中6种关键剪接因子表达失调。我们把这种失调称为
AA特异性剪接变体的相关产生作为“PCa差异中的AA剪接因子编码”。
尽管取得了这些进展,但仍有一些问题没有得到解决。第一,什么是
6种剪接因子表达失调的机制?二、能否生产AA专用
通过外显子跳跃的剪接变异体是否直接归因于6种失调的剪接因子?最后,
PIK 3CD和FGFR 3的AA特异性短变体的编码蛋白介导更致癌的细胞凋亡。
PCa细胞的表型?本申请的目的是解决这些问题,并提供一个
在选择性RNA剪接中与人群相关差异的机制框架,预计
促进未来可药物靶点的鉴定(例如剪接因子和/或产生的剪接变体蛋白)
AA肿瘤表型和差异。
项目成果
期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Genomics of Black American colon cancer disparities: An RNA sequencing (RNA-Seq) study from an academic, tertiary referral center.
- DOI:10.1016/j.surg.2021.03.031
- 发表时间:2021-10
- 期刊:
- 影响因子:3.8
- 作者:Haskins IN;Wang BD;Bernot JP;Cauley E;Horvath A;Marks JH;Lee NH;Agarwal S
- 通讯作者:Agarwal S
Biochemistry and Molecular Biology of Flaviviruses.
- DOI:10.1021/acs.chemrev.7b00719
- 发表时间:2018-04-25
- 期刊:
- 影响因子:62.1
- 作者:Barrows NJ;Campos RK;Liao KC;Prasanth KR;Soto-Acosta R;Yeh SC;Schott-Lerner G;Pompon J;Sessions OM;Bradrick SS;Garcia-Blanco MA
- 通讯作者:Garcia-Blanco MA
Differences in the Platelet mRNA Landscape Portend Racial Disparities in Platelet Function and Suggest Novel Therapeutic Targets.
- DOI:10.1002/cpt.2363
- 发表时间:2021-09
- 期刊:
- 影响因子:6.7
- 作者:Garofano, Kaitlin;Park, C. Sehwan;Alarcon, Cristina;Avitia, Juan;Barbour, April;Diemert, David;Fraser, Claire M.;Friedman, Paula N.;Horvath, Anelia;Rashid, Kameron;Shaazuddin, Mohammed;Sidahmed, Alfateh;O'Brien, Travis J.;Perera, Minoli A.;Lee, Norman H.
- 通讯作者:Lee, Norman H.
Prostate cancer cell-platelet bidirectional signaling promotes calcium mobilization, invasion and apoptotic resistance via distinct receptor-ligand pairs.
- DOI:10.1038/s41598-023-29450-x
- 发表时间:2023-02-17
- 期刊:
- 影响因子:4.6
- 作者:Garofano, Kaitlin;Rashid, Kameron;Smith, Michael;Brantner, Christine;Suwunnakorn, Sumanun;Diemert, David;Gordon, Olivia;Horvath, Anelia;Khan, Sikandar;Popratiloff, Anastas;Rhim, Johng;Sidahmed, Alfateh;Maggirwar, Sanjay B.;O'Brien, Travis J.;Perera, Minoli A.;Lee, Norman H.
- 通讯作者:Lee, Norman H.
Aberrant RNA Splicing in Cancer and Drug Resistance.
- DOI:10.3390/cancers10110458
- 发表时间:2018-11-20
- 期刊:
- 影响因子:5.2
- 作者:Wang BD;Lee NH
- 通讯作者:Lee NH
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Mariano A. Garcia-Blanco其他文献
Protein–protein interactions and 5'-splice-site recognition in mammalian mRNA precursors
哺乳动物 mRNA 前体中的蛋白质-蛋白质相互作用和 5'-剪接位点识别
- DOI:
10.1038/368119a0 - 发表时间:
1994-03-10 - 期刊:
- 影响因子:48.500
- 作者:
Jhumku D. Kohtz;Sharon F. Jamison;Cindy L. Will;Ping Zuo;Reinhard Lührmann;Mariano A. Garcia-Blanco;James L. Manley - 通讯作者:
James L. Manley
867. Spliceosome Mediated RNA Trans-Splicing To Increase Blood Levels of Apolipoprotein A-I and High Density Lipoproteins
- DOI:
10.1016/j.ymthe.2006.08.955 - 发表时间:
2006-01-01 - 期刊:
- 影响因子:
- 作者:
Madaiah Puttaraju;Jun Wang;Alan T. Remaley;Bryan H. Brewer;Mariano A. Garcia-Blanco;Gerard J. McGarrity - 通讯作者:
Gerard J. McGarrity
868. Novel Strategies To Inhibit Ocular Neovascularization Based on Sonic Hedgehog Pathway Blockade
- DOI:
10.1016/j.ymthe.2006.08.956 - 发表时间:
2006-01-01 - 期刊:
- 影响因子:
- 作者:
Madaiah Puttaraju;Jun Wang;Alan T. Remaley;Bryan H. Brewer;Mariano A. Garcia-Blanco;Gerard J. McGarrity - 通讯作者:
Gerard J. McGarrity
Broad-spectrum antiviral ferruginol analog affects the viral proteins translation and actin remodeling during dengue virus infection
广谱抗病毒铁醇类似物影响登革热病毒感染期间的病毒蛋白翻译和肌动蛋白重塑
- DOI:
10.1016/j.antiviral.2025.106139 - 发表时间:
2025-05-01 - 期刊:
- 影响因子:4.000
- 作者:
Vicky C. Roa-Linares;Liliana A. Betancur-Galvis;Miguel A. González-Cardenete;Mariano A. Garcia-Blanco;Juan C. Gallego-Gomez - 通讯作者:
Juan C. Gallego-Gomez
Host RNA-binding proteins and specialized viral RNA translation mechanisms: Potential antiviral targets
宿主 RNA 结合蛋白和专门的病毒 RNA 翻译机制:潜在的抗病毒靶点
- DOI:
10.1016/j.antiviral.2025.106142 - 发表时间:
2025-05-01 - 期刊:
- 影响因子:4.000
- 作者:
Leandro Fernández-García;Mariano A. Garcia-Blanco - 通讯作者:
Mariano A. Garcia-Blanco
Mariano A. Garcia-Blanco的其他文献
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{{ truncateString('Mariano A. Garcia-Blanco', 18)}}的其他基金
Research Project 2: Role of Posttranscriptional Regulatory Networks in the Pathogenesis of Ebola Virus Disease
研究项目2:转录后调控网络在埃博拉病毒疾病发病机制中的作用
- 批准号:
10188760 - 财政年份:2021
- 资助金额:
$ 35.74万 - 项目类别:
Research Project 2: Role of Posttranscriptional Regulatory Networks in the Pathogenesis of Ebola Virus Disease
研究项目2:转录后调控网络在埃博拉病毒疾病发病机制中的作用
- 批准号:
10602493 - 财政年份:2021
- 资助金额:
$ 35.74万 - 项目类别:
Research Project 2: Role of Posttranscriptional Regulatory Networks in the Pathogenesis of Ebola Virus Disease
研究项目2:转录后调控网络在埃博拉病毒疾病发病机制中的作用
- 批准号:
10394321 - 财政年份:2021
- 资助金额:
$ 35.74万 - 项目类别:
Consequences and mechanism of aberrant splicing in African American prostate cancer disparities
非裔美国人前列腺癌差异中异常剪接的后果和机制
- 批准号:
9884534 - 财政年份:2017
- 资助金额:
$ 35.74万 - 项目类别:
Fourth Pan American Dengue Research Network Meeting
第四届泛美登革热研究网络会议
- 批准号:
8836790 - 财政年份:2014
- 资助金额:
$ 35.74万 - 项目类别:
Targeting host 3'-5' exonucleases required for flaviviral infection
靶向黄病毒感染所需的宿主 3-5 核酸外切酶
- 批准号:
8540496 - 财政年份:2012
- 资助金额:
$ 35.74万 - 项目类别:
IsoCyte Laser Scanning Plate Cytometer for High-throughput, High-content Assays
IsoCyte 激光扫描板细胞仪用于高通量、高内涵分析
- 批准号:
8052318 - 财政年份:2011
- 资助金额:
$ 35.74万 - 项目类别:
Alternative splicing and epithelial-mesenchymal plasticity in prostate tumors
前列腺肿瘤中的选择性剪接和上皮间质可塑性
- 批准号:
7991827 - 财政年份:2008
- 资助金额:
$ 35.74万 - 项目类别:
Integrated instrument system for maintenance and delivery of RNAi libraries
用于维护和交付 RNAi 文库的集成仪器系统
- 批准号:
7388756 - 财政年份:2008
- 资助金额:
$ 35.74万 - 项目类别:
Alternative splicing and epithelial-mesenchymal plasticity in prostate tumors
前列腺肿瘤中的选择性剪接和上皮间质可塑性
- 批准号:
8196869 - 财政年份:2008
- 资助金额:
$ 35.74万 - 项目类别:
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