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

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

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Guisheng Song其他文献

Guisheng Song的其他文献

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{{ 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:

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