MicroRNA-15a/16-mediated cytokine/chemokine reprogramming in Kupffer cells prevents the development of hepatocellular carcinoma
MicroRNA-15a/16 介导的库普弗细胞细胞因子/趋化因子重编程可预防肝细胞癌的发展
基本信息
- 批准号:10688153
- 负责人:
- 金额:$ 36.5万
- 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:2022-08-22 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AttenuatedAutomobile DrivingBloodCRISPR/Cas technologyCell SeparationCell TherapyCellsCountryCytotoxic T-LymphocytesDataDevelopmentDiethylnitrosamineEtiologyExperimental DesignsGenetic TranscriptionGoalsGrantGrowthHepaticHepatocyteHomologous GeneImmuneImmunosuppressionImmunotherapyImpairmentIn VitroIncidenceInjectionsKupffer CellsLiverLiver neoplasmsMalignant NeoplasmsMediatingMessenger RNAMicroRNAsMusNRAS geneObesityOncogenesOncogenicPatientsPrimary carcinoma of the liver cellsProcessProductionRegulatory T-LymphocyteResearchRoleSerumSignal TransductionT-Cell DepletionTechniquesTestingTherapeuticThymomaTimeTransplantationTumor BurdenTumor ImmunityViral Oncogenebeta-Chemokinesc-myc Genescell motilitychemokinechemokine receptorcytokinedesigngamma-Chemokinesin vivo Modelineffective therapiesinsightknock-downliver cancer modelmigrationmortalitymouse modelnew therapeutic targetnovelpreventrecruitsuccesstherapeutic miRNAtherapeutic targettranscriptometumor
项目摘要
Abstract
Hepatocellular carcinoma (HCC) ranks the third in cancer-related mortality because of ineffective therapy.
Intratumoral accumulation of regulatory T-cells (Tregs), which suppresses antitumor immunity, has been identified
in HCC. Despite the extensive research of microRNAs in HCC, their roles in regulating immunosuppression are
poorly described. Aberrant activation of AKT (v-akt murine thymoma viral oncogene homolog 1) and Nras
(neuroblastoma ras viral oncogene homolog) (Ras) was observed in Kupffer cells (KCs) and hepatocytes (HCs)
in 74% of HCC patients. Hydrodynamic injection (HDI) of activated forms of AKT and Nras (AKT/Ras) into mice
triggered the development of lethal HCC within 6-8 weeks. MiRNA profiling revealed that miR-15a and miR-16-
1 cluster (miR-15a/16) was reduced in KCs from HCC tumors of AKT/Ras mice and patients. KC-specific
expression of miR-15a/16 fully prevented growth of aggressive HCC in AKT/Ras mice, while 100% of AKT/Ras
mice died from lethal tumor burden within 6-8 weeks post-injection. KC-specific expression of miR-15a/16 also
led to a significant regression of HCC tumors in AKT/Ras mice bearing tumors. Mechanistically, AKT/Ras
reprogrammed the transcriptome of KCs toward M2 polarization of KCs and drove a significant increase in serum
C-C motif chemokine 22 (CCL22) and mRNA levels of Ccl22 in KCs of AKT/Ras mice. In contrast, miR-15a/16
reversed this process and inhibited CCL22 overproduction by directly targeting NF-κB that activates transcription
of Ccl22. CCL22 recruits Tregs via CCR4 (C-C chemokine receptor type 4). Indeed, additional treatment of CCL22
recovered immunosuppression and growth of HCC that was fully prevented by miR-15a/16 in AKT/Ras mice.
We hypothesize that AKT/Ras-educated KCs initiate hepatic recruitment of Tregs by overproducing CCL22,
thereby promoting HCC development; while KC-specific expression of miR-15a/16 suppresses hepatic recruitment
of Tregs and HCC development by attenuating CCL22 production. The objective of this project is to elucidate the
role of AKT/Ras-educated KCs in promoting immune suppression that promotes growth of HCC, while miR-15a/16
reverses this process by inhibiting NF-κB signaling in KCs. The long-time goal is to develop KCs as a therapeutic
target and miR-15a/16 as a novel immunotherapy against HCC. Three specific aims are designed to test our
hypothesis. Specifically, we will (1) unravel the mechanism(s) by which AKT/Ras-educated KCs promote
immunosuppression and HCC development. (2) establish the mechanism(s) by which miR-15a/16 drives
antitumor immunity; and (3) evaluate the therapeutic potential of miR-15a/16 against HCC with divergent
backgrounds. The combination of strong preliminary data and a logical and rationally based experimental design
make this project highly feasible. We expect that this study will provide a novel insight into the immunosuppression
mechanisms in HCC and facilitate the design of KCs as a novel therapeutic target and miR-15a/16 as a rational
immunotherapy against HCC.
摘要
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Guisheng Song其他文献
Guisheng Song的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Guisheng Song', 18)}}的其他基金
MicroRNA-15a/16-mediated cytokine/chemokine reprogramming in Kupffer cells prevents the development of hepatocellular carcinoma
MicroRNA-15a/16 介导的库普弗细胞细胞因子/趋化因子重编程可预防肝细胞癌的发展
- 批准号:
10518314 - 财政年份:2022
- 资助金额:
$ 36.5万 - 项目类别:
miR-378/378* promotes hepatic lipid accumulation and progression of NAFLD to NASH
miR-378/378*促进肝脏脂质积累以及NAFLD向NASH的进展
- 批准号:
8749884 - 财政年份:2014
- 资助金额:
$ 36.5万 - 项目类别:
miR-378/378* promotes hepatic lipid accumulation and progression of NAFLD to NASH
miR-378/378*促进肝脏脂质积累以及NAFLD向NASH的进展
- 批准号:
9336294 - 财政年份:2014
- 资助金额:
$ 36.5万 - 项目类别:
miR-378/378* promotes hepatic lipid accumulation and progression of NAFLD to NASH
miR-378/378*促进肝脏脂质积累以及NAFLD向NASH的进展
- 批准号:
8912467 - 财政年份:2014
- 资助金额:
$ 36.5万 - 项目类别:
相似海外基金
Establishment of a method for evaluating automobile driving ability focusing on frontal lobe functions and its application to accident prediction
以额叶功能为中心的汽车驾驶能力评价方法的建立及其在事故预测中的应用
- 批准号:
20K07947 - 财政年份:2020
- 资助金额:
$ 36.5万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Evaluation of the Effectiveness of Multi-Professional Collaborative Assessment of Cognitive Function and Automobile Driving Skills and Comprehensive Support
认知功能与汽车驾驶技能多专业协同评估效果评价及综合支持
- 批准号:
17K19824 - 财政年份:2017
- 资助金额:
$ 36.5万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
Development of Flexible Automobile Driving Interface for Disabled People
残疾人灵活汽车驾驶界面开发
- 批准号:
25330237 - 财政年份:2013
- 资助金额:
$ 36.5万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Automobile driving among older people with dementia: the effect of an intervention using a support manual for family caregivers
患有痴呆症的老年人的汽车驾驶:使用家庭护理人员支持手册进行干预的效果
- 批准号:
23591741 - 财政年份:2011
- 资助金额:
$ 36.5万 - 项目类别:
Grant-in-Aid for Scientific Research (C)