染色质结构蛋白HMGA2通过抑制IGFBP3转录的新机制促进胶质瘤恶性

IF 2.9 4区医学 Q2 PATHOLOGY

Pathology, research and practice Pub Date : 2025-05-27 DOI:10.1016/j.prp.2025.156051

Zenghua Liang , Lu Qiao , Pengyi Ma , Shanshan Zhang , Cuiyun Sun , Wenjun Luo , Lin Yu

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引用次数: 0

摘要

神经胶质瘤是最常见的原发性脑肿瘤，其特点是快速增殖、侵袭性生长模式和临床预后差。本研究探讨染色质结构蛋白高迁移率组AT-hook 2 （HMGA2）在胶质瘤中的表达及其临床意义，旨在寻找潜在的预后生物标志物和治疗靶点。方法采用免疫组化（IHC）方法分析HMGA2在不同级别胶质瘤组织中的表达。HMGA2在胶质瘤细胞中的功能通过迁移、侵袭、增殖和原位肿瘤移植实验进行了鉴定。通过RNA-Seq筛选HMGA2的下游基因。采用染色质免疫沉淀-定量聚合酶链反应（ChIP-qPCR）、电泳迁移位移法（EMSA）和染色体构象捕获法（3 C）分析了HMGA2在胶质瘤细胞中的下游机制。结果通过免疫组化分析，我们发现HMGA2表达水平与胶质瘤恶性程度呈正相关。多因素COX回归分析进一步证实HMGA2是胶质瘤的独立预后因素。我们的功能研究表明，HMGA2显著增强胶质母细胞瘤（GBM）细胞的迁移、侵袭和增殖能力。在机制上，我们发现胰岛素样生长因子结合蛋白3 （IGFBP3）是HMGA2的一个新的下游靶点。HMGA2通过破坏启动子-增强子相互作用介导IGFBP3的转录抑制，导致随后PI3K/Akt信号通路的激活，促进GBM的恶性表型。结论证实了一种新的染色质构象介导的HMGA2转录抑制机制。HMGA2通过调节IGFBP3的表达和PI3K/Akt通路，成为胶质瘤患者预后的生物标志物和潜在的治疗靶点。

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Chromatin architecture protein HMGA2 promotes glioma malignancy via novel mechanism of IGFBP3 transcription inhibition

Background

Glioma, the most prevalent primary brain tumor, is characterized by rapid proliferation, invasive growth patterns, and poor clinical outcomes. This study investigates the expression and clinical significance of chromatin architecture protein high mobility group AT-hook 2 (HMGA2) in glioma, aiming to identify potential prognostic biomarkers and therapeutic targets.

Methods

The expression of HMGA2 in different grades glioma samples was analyzed by immunohistochemistry (IHC). The functions of HMGA2 in glioma cells were identified by migration, invasion, proliferation and orthotopic tumor transplantation assays. The downstream genes of HMGA2 were screened by RNA-Seq. Chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR), electrophoretic mobility shift assay (EMSA) and chromosome conformation capture assay (3 C) were used to analyze the downstream mechanism of HMGA2 in glioma cells.

Results

We demonstrated a positive correlation between HMGA2 expression levels and glioma malignancy grade through IHC analysis. Multivariate COX regression analysis further established HMGA2 as an independent prognostic factor in glioma. Our functional studies revealed that HMGA2 significantly enhances the migration, invasion, and proliferation capabilities of glioblastoma (GBM) cells. Mechanistically, we identified insulin-like growth factor binding protein 3 (IGFBP3) as a novel downstream target of HMGA2. HMGA2 mediates transcriptional repression of IGFBP3 through disruption of promoter-enhancer interactions, leading to subsequent activation of the PI3K/Akt signaling pathway and promotion of malignant phenotypes in GBM.

Conclusion

We confirmed a novel chromatin conformation-mediated transcriptional repression mechanism of HMGA2. By regulating IGFBP3 expression and modulating the PI3K/Akt pathway, HMGA2 emerges as a promising prognostic biomarker and potential therapeutic target for glioma patients.

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来源期刊

Pathology, research and practice 医学-病理学

CiteScore

5.00

自引率

3.60%

发文量

405

审稿时长

24 days

期刊介绍： Pathology, Research and Practice provides accessible coverage of the most recent developments across the entire field of pathology: Reviews focus on recent progress in pathology, while Comments look at interesting current problems and at hypotheses for future developments in pathology. Original Papers present novel findings on all aspects of general, anatomic and molecular pathology. Rapid Communications inform readers on preliminary findings that may be relevant for further studies and need to be communicated quickly. Teaching Cases look at new aspects or special diagnostic problems of diseases and at case reports relevant for the pathologist''s practice.