The miR-192/EGR1-HOXB9 loop inhibits immune evasion in glioma by arresting their NSC phenotypes

IF 4.8 2区 医学 Q2 IMMUNOLOGY International immunopharmacology Pub Date : 2025-03-15 DOI:10.1016/j.intimp.2025.114453
Guo-Wei Li , Yan-Ping Jin , Min-Feng Sheng
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Abstract

Objective

To elucidate the mechanism by which the miR-192-related axis regulates glioma immune evasion.

Methods

Factor expression was measured by PCR/Western Blotting (WB). Immunofluorescence, FISH and DLRTM were used to elucidate target regulation mechanisms. Mitophagy was observed by TEM. We performed BrdU/Transwell assays to evaluate malignant phenotypes and WB to measure stemness-related protein expression in glioma. Immune chemokine levels were measured by ELISA, and M2-TAM/CD8+ T-cell proportions were measured by immune-fluorescence. Growth curves/tumor volume in vivo and tumor weight in vitro were assessed to evaluate tumor growth in vivo. An immune microenvironment was established in nude mice via tail vein injection of immune cells. Masson's trichrome staining was performed to explore the degree of fibrosis in relevant tissues.

Results

MiR-192 expression was negatively correlated with glioma malignancy. The expression of downstream regulator (EGR1/HOXB9) of miR-192 was positively correlated with malignant phenotypes. MiR-192 inhibited EGR1/HOXB9 through targeted binding. The miR-192/EGR1-HOXB9 loop induced mitophagy, thus inhibited glioma cell proliferation/invasion. Moreover, this loop inhibited MT, weakening glioma cell stemness. This pathway reduced M2-TAM numbers and weakened their inhibitory effect on CD8+ T-cells by regulating immune chemokines. In vivo, miR-192 inhibited glioma proliferation and induced immune infiltration into glioma through this loop.

Conclusion

The miR-192/EGR1-HOXB9 loop inhibited glioma stemness phenotypes, weakening glioma malignancy by regulating mitophagy. Moreover, this loop affected chemokine secretion by TAMs, weakened their inhibitory effect on CD8+ T-cells and reduced immune evasion in glioma by regulating MT.
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方法通过PCR/Western Blotting(WB)检测因子表达。免疫荧光、FISH 和 DLRTM 用于阐明靶调控机制。通过 TEM 观察了有丝分裂。我们进行了BrdU/Transwell检测以评估恶性表型,并进行了WB检测以测量胶质瘤中干性相关蛋白的表达。免疫趋化因子水平通过ELISA测定,M2-TAM/CD8+ T细胞比例通过免疫荧光测定。评估了体内生长曲线/肿瘤体积和体外肿瘤重量,以评价体内肿瘤生长情况。通过尾静脉注射免疫细胞在裸鼠体内建立免疫微环境。结果 MiR-192 的表达与胶质瘤的恶性程度呈负相关。miR-192下游调控因子(EGR1/HOXB9)的表达与恶性表型呈正相关。MiR-192 通过靶向结合抑制 EGR1/HOXB9。miR-192/EGR1-HOXB9 环路可诱导有丝分裂,从而抑制胶质瘤细胞的增殖/侵袭。此外,这一环路还抑制了MT,削弱了胶质瘤细胞的干性。这一途径通过调节免疫趋化因子,减少了 M2-TAM 的数量,削弱了它们对 CD8+ T 细胞的抑制作用。结论 miR-192/EGR1-HOXB9 环路抑制了胶质瘤干性表型,通过调节有丝分裂来削弱胶质瘤的恶性程度。此外,这一环路还影响了 TAMs 的趋化因子分泌,削弱了它们对 CD8+ T 细胞的抑制作用,并通过调节 MT 减少了胶质瘤的免疫逃避。
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来源期刊
CiteScore
8.40
自引率
3.60%
发文量
935
审稿时长
53 days
期刊介绍: International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.
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