SHH激活型髓母细胞瘤中miRNA表达失调的分子机制

doi:10.3969/j.issn.1674-8115.2026.01.001

上海交通大学学报（医学版） ›› 2026, Vol. 46 ›› Issue (1): 1-14.doi: 10.3969/j.issn.1674-8115.2026.01.001

• 创新团队成果专栏 •

SHH激活型髓母细胞瘤中miRNA表达失调的分子机制

朱颖, 隋怡, 唐玉杰()

上海交通大学基础医学院组织胚胎学与遗传发育学系，上海 200025

收稿日期:2025-07-02 接受日期:2025-11-25 出版日期:2026-01-28 发布日期:2026-01-30
通讯作者: 唐玉杰，研究员，博士；电子信箱：yujietang@shsmu.edu.cn。
作者简介:第一联系人：朱颖参与实验设计、实验实施、数据分析、论文写作与修改，隋怡参与前期实验设计与实施、论文的写作及修改，唐玉杰全程指导课题开展、论文写作与修改。所有作者均阅读并同意了最终稿件的提交。
基金资助:
国家自然科学基金(82473455);国家自然科学基金(82293661)

Molecular mechanisms of miRNA expression dysregulation in SHH-activated subtype medulloblastoma

Zhu Ying, Sui Yi, Tang Yujie()

Department of Histoembryology and Genetic Development, Shanghai Jiao Tong University College of Basic Medical Sciences, Shanghai 200025, China

Received:2025-07-02 Accepted:2025-11-25 Online:2026-01-28 Published:2026-01-30
Contact: Tang Yujie, E-mail: yujietang@shsmu.edu.cn.
About author:First author contact:Zhu Ying participated in experiment design, experiment implementation, data analysis, and paper writing and modification. Sui Yi participated in the preliminary experimental design and implementation, as well as paper writing and revision. Tang Yujie supervised the whole project development, and paper writing and revision. All authors have read the last version of paper and consented to submission.
Supported by:
National Natural Science Foundation of China(82473455)

摘要/Abstract

摘要：

目的·探究miRNA表达失调在SHH激活型髓母细胞瘤（sonic hedgehog-activated subtype medulloblastoma，SHH-MB）中的作用，并比较裸鼠皮下同种异体移植模型与实体瘤患者的失调miRNA的相关特征。方法·使用鼠源SHH-MB细胞系（SmoWT和SMB56）建立裸鼠皮下同种异体移植模型。每种模型被随机分为以平滑蛋白受体抑制剂（smoothened inhibitor，SMOi）GDC-0449灌胃处理的实验组、以二甲基亚砜（dimethyl sulfoxide，DMSO）灌胃的对照组，并收取这4组裸鼠的肿瘤样本。采集出生后7 d（P7）及60 d（P60）的正常裸鼠的小脑组织作为P7正常小脑、P60正常小脑组。参照肿瘤样本，收取GDC-0449灌胃处理的P7正常裸鼠的小脑组织（P7小脑给药组）以及DMSO灌胃处理的P7正常裸鼠的小脑组织（P7小脑对照组）。分别采用mRNA测序（mRNA sequencing，mRNA-seq）和miRNA测序（microRNA sequencing，miRNA-seq）获得以上8组样本的mRNA和miRNA表达数据并进行样本表达谱相关性分析。通过差异表达分析系统解析：① 鼠源SHH-MB模型的肿瘤核心转录组特征。② 正常小脑发育相关的转录组特征。③ 肿瘤及发育小脑中Hedgehog（Hh）通路依赖和非Hh通路依赖的转录组特征。利用miRDB、TargetScan与miRTarBase数据库并结合mRNA差异表达结果，预测关键差异miRNA的靶基因。通过京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes，KEGG）富集分析，解析靶基因涉及的核心信号通路。针对在P7发育小脑中鉴定到的Hh通路依赖的miR-204-5p，进行靶基因预测与靶基因KEGG通路富集分析。最后，搜集R2与基因表达综合数据库（Gene Expression Omnibus，GEO）中SHH-MB患者肿瘤及健康对照小脑的mRNA与miRNA表达数据，通过差异表达分析与韦恩分析评估差异表达miRNAs/mRNAs调控关系在人与小鼠之间的保守性。结果·样本mRNA表达谱相关性分析显示，SmoWT对照组与SMB56对照组的mRNA表达谱相似性较高；2个对照组与P7正常小脑组的相似性高于P60正常小脑组，而GDC-0449处理未显著改变这2个对照组的整体转录组特征。miRNA表达谱相关性分析结果与mRNA层面类似。SmoWT对照组、SMB56对照组与P7正常小脑、P60正常小脑组的差异表达分析鉴定出2个对照组中共同显著上调的95个miRNA、下调的126个miRNA；其中50个上调miRNA和38个下调miRNA在P7与P60正常小脑比较中同向表达。通过SmoWT实验组与SmoWT对照组、SMB56实验组与SMB56对照组的差异表达分析，鉴定出各模型中Hh通路与非Hh通路依赖的miRNA。韦恩分析显示，Hh通路依赖的miRNA（占差异miRNA总数的10%~20%）在模型间重叠极少；非Hh通路依赖的miRNA则在模型间高度保守。Hh通路依赖的差异表达miRNA的靶基因的KEGG通路富集结果显示，其富集于磷脂酰肌醇3激酶/蛋白激酶B信号通路（phosphoinositide 3-kinase/protein kinase B pathway，PI3K/AKT）、磷脂酶D（phospholipase D，PLD）、RAS/丝裂原活化蛋白激酶信号通路（RAS/mitogen-activated protein kinase pathway，RAS/MAPK）和DNA复制（DNA replication）通路。通过比较P7小脑给药组与P7小脑对照组，鉴定出P7小脑中7个Hh通路激活和1个Hh通路抑制的miRNA，285个Hh通路激活和72个Hh通路抑制的mRNA。miR-204-5p的靶基因富集于细胞周期通路。SHH-MB患者肿瘤与健康小脑对照样本的差异表达分析鉴定出22个人鼠保守的miRNA，其靶基因富集于环磷腺苷（cyclic adenosine monophosphate，cAMP）和细胞周期通路等。结论·鼠源SHH-MB模型表现出广泛的miRNA表达失调，但SMOi处理仅对其中小部分失调miRNA有逆转作用，提示Hh通路对miRNA失调的影响有限，并且仅有非Hh通路依赖的失调miRNA在2个鼠源模型之间表现出部分重叠。此外，SHH-MB鼠源模型与实体瘤患者来源的肿瘤有保守的失调miRNA特征。

关键词: SHH激活型髓母细胞瘤, Hedgehog通路, miRNA表达失调, 小脑发育

Abstract:

Objective ·To investigate the role of miRNA expression dysregulation in sonic hedgehog-activated subtype medulloblastoma (SHH-MB), and to compare the dysregulated miRNA features between subcutaneous xenograft models in nude mice and patients with solid tumors. Methods ·Mouse SHH-MB cell lines (SmoWT and SMB56) were used to establish subcutaneous xenograft models in nude mice. For each model, mice were randomly divided into groups treated with the smoothened inhibitor (SMOi) GDC-0449 (SmoWT experimental group and SMB56 experimental group) or dimethyl sulfoxide (DMSO) (SmoWT control group and SMB56 control group), and tumor samples from these 4 groups were collected. Cerebellar tissues from normal P7 (postnatal day 7) and P60 nude mice were collected as controls (P7 normal cerebellum group and P60 normal cerebellum group). Following the same procedure, cerebellar tissues were also collected from P7 normal nude mice treated with GDC-0449 (P7 cerebellum treatment group) or DMSO (P7 cerebellum control group). mRNA sequencing (mRNA-seq) and microRNA sequencing (miRNA-seq) were performed on these eight sample groups to obtain mRNA and miRNA expression profiles. Subsequently, differential expression analysis was systematically employed to elucidate: ① the core transcriptomic features of tumors in mouse SHH-MB models; ② transcriptomic features associated with normal cerebellar development; ③ Hedgehog (Hh)-dependent and Hh-independent transcriptomic features in both tumors and developing cerebellum. Target genes of key differentially expressed miRNAs were predicted by integrating data from the miRDB, TargetScan, and miRTarBase databases, combined with mRNA differential expression results. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was then performed to identify core signaling pathways involving these target genes. Specifically, for the Hh-dependent miRNA miR-204-5p identified in the P7 developing cerebellum, target genes were predicted and subjected to KEGG pathway enrichment analysis. Finally, mRNA and miRNA expression profiles from SHH-MB patient tumors and healthy control cerebella were obtained from the R2 and Gene Expression Omnibus (GEO). Conservation of differentially expressed miRNAs/mRNAs and their regulatory relationships between humans and mice was then systematically assessed through differential expression and Venn analysis. Results ·Analysis of mRNA expression profile correlations revealed a high correlation between the SmoWT control and SMB56 control groups. Both tumor control groups showed higher correlation with the P7 normal cerebellum group than with the P60 normal cerebellum group. Treatment with GDC-0449 did not significantly alter the overall transcriptomic profiles of either control group. The miRNA expression profile correlation results were consistent with those observed in the mRNA profiles. Differential expression analysis comparing the SmoWT control and SMB56 control groups with the P7 and P60 normal cerebellum groups identified 95 commonly upregulated and 126 commonly downregulated miRNAs in the two control groups. Among these, 50 upregulated and 38 downregulated miRNAs showed the same expression trends in the P7 and P60 normal cerebellum comparison. Differential expression analysis between the SmoWT experimental and control groups and between the SMB56 experimental and control groups identified Hh-dependent and Hh-independent differentially expressed miRNAs in each model. Venn diagram showed that the Hh-dependent miRNAs (accounting for 10%-20% of all differentially expressed miRNAs) showed minimal overlap between mouse SHH-MB models, whereas Hh-independent miRNAs were highly conserved across models. KEGG pathway enrichment analysis of the target genes of Hh-dependent differentially expressed miRNAs showed significant enrichment in the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, phospholipase D (PLD) pathway, RAS/mitogen-activated protein kinase (RAS/MAPK) pathway, and DNA replication pathways. Comparison between the P7 cerebellum treatment group and the P7 cerebellum control group identified 7 miRNAs and 285 mRNAs whose expression was promoted by the Hh pathway, and 1 miRNA and 72 mRNAs whose expression was inhibited by the Hh pathway in the P7 cerebellum. The target genes of miR-204-5p were enriched in the cell cycle pathway. Differential expression analysis of SHH-MB patient tumors vs healthy cerebellar controls identified 22 conserved human‑mouse miRNAs, with their target genes enriched in the cyclic adenosine monophosphate (cAMP) signaling pathway and the cell cycle pathway. Conclusion ·Mouse SHH-MB models exhibit extensive miRNA expression dysregulation. However, SMOi treatment reverses only a small subset of these dysregulated miRNAs, indicating a limited effect of the Hh pathway on miRNA dysregulation. Only Hh-independent dysregulated miRNAs show partial overlap between mouse SHH-MB models. Furthermore, there are conserved dysregulated miRNA features between mouse SHH-MB models and patients with solid tumors.

Key words: sonic hedgehog-activated subtype medulloblastoma (SHH-MB), Hedgehog pathway, miRNA expression dysregulation, cerebellar development

中图分类号:

R739.41

朱颖, 隋怡, 唐玉杰. SHH激活型髓母细胞瘤中miRNA表达失调的分子机制[J]. 上海交通大学学报（医学版）, 2026, 46(1): 1-14.

Zhu Ying, Sui Yi, Tang Yujie. Molecular mechanisms of miRNA expression dysregulation in SHH-activated subtype medulloblastoma[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026, 46(1): 1-14.

图/表 6

图1 miRNA合成与功能相关的基因在鼠源SHH-MB中的依赖性分析Note： A. Venn diagram of shared essential genes identified by CRISPR-Cas9 screening under in vitro and in vivo conditions in SmoWT and SMB56 cells. B. Detailed screening results for miRNA biogenesis genes Drosha, Dgcr8, Ago2, Dicer1, and Tarbp2. Genes were ranked by RRA score, which denotes gene essentiality, with lower scores representing stronger essentiality in the negative selection screen. C. Read count changes of sgRNAs targeting Drosha and Dgcr8.

Fig 1 Dependency analysis of miRNA biogenesis genes in mouse SHH-MB models

图2 鼠源SHH-MB模型与裸鼠正常小脑的mRNA转录组，以及Hh通路转录因子和miRNA生物合成相关基因的mRNA表达水平比较Note： A. Correlation analysis of mRNA expression profiles across sample groups, including SHH-MB tumors (SmoWT and SMB56 models with or without GDC-0449 treatment) and normal cerebellum (P7 and P60). B/C. Venn diagrams of the overlap of up-regulated mRNAs (B) and down-regulated mRNAs (C) among tumors vs P7 cerebellum, tumors vs P60 cerebellum, and P7 cerebellum vs P60 cerebellum. D. Expression levels of Gli1, Gli2, Drosha, Dgcr8, Tarbp2, Dicer1, Xpo5, and Ago2 in the indicated groups.

Fig 2 Comparison of mRNA transcriptomes between mouse SHH-MB models and normal nude mouse cerebellum, and mRNA expression levels of Hh pathway transcription factors and miRNA biogenesis genes

图3 鼠源SHH-MB模型与裸鼠正常小脑的miRNA转录组比较及差异表达miRNA的DO富集分析Note： A. Correlation analysis of miRNA expression profiles across sample groups, including SHH-MB tumors (SmoWT and SMB56 models with or without GDC-0449 treatment) and normal cerebellum (P7 and P60). B/C. Venn diagrams of the overlap of up-regulated miRNAs (B) and down-regulated miRNAs (C) among tumors vs P7 cerebellum, tumors vs P60 cerebellum, and P7 cerebellum vs P60 cerebellum. D/E. DO enrichment analysis of miRNAs consistently up-regulated (D) or down-regulated (E) in both mouse SHH-MB models.

Fig 3 Comparison of miRNA transcriptomes between mouse SHH-MB models and normal nude mouse cerebellum, and DO enrichment analysis of differentially expressed miRNAs

图4 鼠源SHH-MB模型中差异表达miRNAs/mRNAs的Hh通路依赖性及KEGG通路富集分析Note： A/B. Identification and overlap of Hh-dependent and Hh-independent tumor-upregulated miRNAs and tumor-downregulated mRNAs (A), and tumor-downregulated miRNAs and tumor-upregulated mRNAs (B). C. KEGG enrichment analysis of predicted target genes of Hh pathway-dependent miRNAs/mRNAs. D. Venn diagrams of the overlap of KEGG terms between mouse SHH-MB models in Fig C. cAMP—cyclic adenosine monophosphate; GnRH—gonadotropin-releasing hormone; HIF-1—hypoxia-inducible factor-1; RAS—rat sarcoma viral oncogene; Rap1—ras-related protein 1; DEmiRNAs—differentially expressed miRNAs.

Fig 4 Hh pathway dependence of differentially expressed miRNAs/mRNAs and KEGG pathway enrichment in mouse SHH-MB models

图5 正常发育小脑中差异表达miRNAs/mRNAs的Hh通路依赖性、与SHH-MB模型的比较及靶基因KEGG通路富集分析Note： A. Correlation analysis of miRNA and mRNA expression profiles across P60 cerebellum and DMSO-treated or GDC-0449-treated P7 cerebellum. B. Identification of Hh pathway-dependent differentially expressed miRNAs in the P7 cerebellum. C. Identification of Hh pathway-dependent differentially expressed mRNAs in the P7 cerebellum. Foxj1—forkhead box J1; Gli2—GLI family zinc finger 2; Ptch2—patched 2; Atoh1—atonal homolog 1; E2f2—E2F transcription factor 2; Usp44—ubiquitin specific peptidase 44; Cdk6—cyclin-dependent kinase 6. D. Venn diagrams of the overlap of Hh pathway-dependent miRNAs and mRNAs among mouse SHH-MB models and the P7 cerebellum. E. Regulatory network of miR-204-5p and its predicted target genes. Tox3—TOX high mobility group box family member 3; Tnfaip8—TNF alpha-induced protein 8; Aurkb—aurora kinase B; Has2—hyaluronan synthase 2; Arhgef39—Rho guanine nucleotide exchange factor 39; Ticam2—TIR domain-containing adaptor molecule 2; Rtkn2—rhotekin 2; Rad51—RAD51 recombinase; Angptl2—angiopoietin-like 2; Cxcr4—C-X-C motif chemokine receptor 4; Esco2—establishment of sister chromatid cohesion N-acetyltransferase 2; Ncapd2—non-SMC condensin I complex subunit D2; Arhgap11a—Rho GTPase-activating protein 11A; Smc2—structural maintenance of chromosomes 2; Ccnd2—cyclin D2; Slc43a1—solute carrier family 43 member 1; Mad2l1—mitotic arrest deficient 2-like 1; Crybg3—crystallin beta-gamma domain containing 3; Dcc—DCC netrin 1 receptor; Cdc25b—cell division cycle 25B. F. KEGG pathway enrichment of the target genes.

Fig 5 Hh pathway dependence of differentially expressed miRNAs/mRNAs in the developing cerebellum, comparison with SHH-MB models, and KEGG pathway enrichment of target genes

图6 SHH-MB患者肿瘤组织miRNAs/mRNAs表达特征及人鼠保守性分析Note： A. mRNA expression of Hh pathway genes (GLI1, GLI2) and miRNA biogenesis genes in SHH-MB patient tumors and normal cerebellum tissues (U133p2 dataset; ①P<0.001, ②P=0.010). B. Correlation analysis of miRNA expression profiles in SHH-MB patient tumors and normal cerebellum tissues (GSE42657 dataset). C. Volcano plot of differentially expressed miRNAs between SHH-MB and normal cerebellum tissues (GSE42657 dataset). FDR—false discovery rate; FC—fold change. D. Conserved differentially expressed miRNAs between SHH-MB patient tumors and mouse SHH-MB models. E. Conserved differentially expressed mRNAs between SHH-MB patient tumors and mouse SHH-MB models. F/G. KEGG pathway enrichment of predicted target genes of conserved up-regulated miRNAs (F) and down-regulated miRNAs (G). AGE—advanced glycation end products; RAGE—receptor for advanced glycation end products; ECM—extracellular matrix.

Fig 6 Expression characteristics of miRNAs/mRNAs in tumor tissues from SHH-MB patients and human-mouse conservation analysis

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SHH激活型髓母细胞瘤中miRNA表达失调的分子机制

Molecular mechanisms of miRNA expression dysregulation in SHH-activated subtype medulloblastoma

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