Identification of CENPM as a key gene driving adrenocortical carcinoma metastasis via physical interaction with immune checkpoint ligand FGL1

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Clinical and Translational Medicine Pub Date : 2025-01-08 DOI:10.1002/ctm2.70182

Cunru Zou, Yu Zhang, Chengyue Liu, Yaxin Li, Congjie Lin, Hao Chen, Jiangping Hou, Guojun Gao, Zheng Liu, Qiupeng Yan, Wenxia Su

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Abstract

Background

Distant metastasis occurs in the majority of adrenocortical carcinoma (ACC), leading to an extremely poor prognosis. However, the key genes driving ACC metastasis remain unclear.

Methods

Weighted gene co-expression network analysis (WGCNA) and functional enrichment analysis were conducted to identify ACC metastasis-related genes. Data from RNA-seq and microarray were analyzed to reveal correlations of the CENPM gene with cancer, metastasis, and survival in ACC. Immunohistochemistry was used to assess CENPM protein expression. The impact of CENPM on metastasis behaviour was verified in ACC (H295R and SW-13) cells and xenograft NPG mice. DIA quantitative proteomics analysis, western blot, immunofluorescence, and co-immunoprecipitation assay were performed to identify the downstream target of CENPM.

Results

Among the 12 035 analyzed genes, 363 genes were related to ACC metastasis and CENPM was identified as the hub gene. CENPM was upregulated in ACC samples and associated with metastasis and poor prognosis. Knockdown of CENPM inhibited proliferation, invasion, and migration of ACC cells and suppressed liver metastasis in xenograft NPG mice. Collagen-containing extracellular matrix signalling was primarily downregulated when CENPM was knocked down. FGL1, important components of ECM signalling and immune checkpoint ligand of LAG3, were downregulated following CENPM silence, overexpressed in human advanced ACC samples, and colocalized with CENPM. Physical interaction between CENPM and FGL1 was identified. Overexpression of FGL1 rescued migration and invasion of CENPM knockdown ACC cells.

Conclusions

CENPM is a key gene in driving ACC metastasis. CENPM promotes ACC metastasis through physical interaction with the immune checkpoint ligand FGL1. CENPM can be used as a new prognostic biomarker and therapeutic target for metastatic ACC.

Highlights

CENPM is the key gene that drives ACC metastasis, and a robust biomarker for ACC prognosis.
Silencing CENPM impedes ACC metastasis in vitro and in vivo by physical interaction with immune checkpoint ligand FGL1.
FGL1 is overexpressed in ACC and promotes ACC metastasis.

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通过与免疫检查点配体FGL1的物理相互作用，发现CENPM是驱动肾上腺皮质癌转移的关键基因。

背景：肾上腺皮质癌（ACC）多发生远端转移，预后极差。然而，驱动ACC转移的关键基因仍不清楚。方法：采用加权基因共表达网络分析（Weighted gene co-expression network analysis， WGCNA）和功能富集分析鉴定ACC转移相关基因。我们分析了RNA-seq和微阵列数据，以揭示CENPM基因与ACC的癌症、转移和生存的相关性。免疫组化检测CENPM蛋白表达。在ACC （H295R和SW-13）细胞和异种移植物NPG小鼠中验证了CENPM对转移行为的影响。采用DIA定量蛋白质组学分析、western blot、免疫荧光、共免疫沉淀等方法鉴定CENPM下游靶点。结果：在分析的12035个基因中，有363个基因与ACC转移相关，以CENPM为中心基因。在ACC样本中，CENPM表达上调，并与转移和不良预后相关。敲低CENPM可抑制异种移植物NPG小鼠ACC细胞的增殖、侵袭和迁移，并抑制肝转移。当CENPM被敲除时，含胶原蛋白的细胞外基质信号主要下调。FGL1是ECM信号和LAG3免疫检查点配体的重要组成部分，在CENPM沉默后下调，在人类晚期ACC样品中过表达，并与CENPM共定位。确定了CENPM与FGL1之间的物理相互作用。FGL1的过表达挽救了CENPM敲低ACC细胞的迁移和侵袭。结论：CENPM是ACC转移的关键基因。CENPM通过与免疫检查点配体FGL1的物理相互作用促进ACC转移。CENPM可作为转移性ACC的新的预后生物标志物和治疗靶点。重点：CENPM是ACC转移的关键基因，也是ACC预后的一个强有力的生物标志物。沉默CENPM通过与免疫检查点配体FGL1的物理相互作用阻碍ACC在体外和体内的转移。FGL1在ACC中过表达并促进ACC转移。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.