Zou Cunru, Zhang Yu, Liu Chengyue, Li Yaxin, Lin Congjie, Chen Hao, Hou Jiangping, Gao Guojun, Liu Zheng, Yan Qiupeng, Su Wenxia
Department of Physiology, School of Basic Medicine, Shandong Second Medical University, Weifang, China.
Department of Pathology, Affiliated Hospital of Shandong Second Medical University, Weifang, China.
Clin Transl Med. 2025 Jan;15(1):e70182. doi: 10.1002/ctm2.70182.
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.
背景：大多数肾上腺皮质癌（ACC）会发生远处转移，导致预后极差。然而，驱动ACC转移的关键基因仍不清楚。 方法：进行加权基因共表达网络分析（WGCNA）和功能富集分析，以鉴定ACC转移相关基因。分析RNA测序和微阵列数据，以揭示CENPM基因与ACC中的癌症、转移和生存的相关性。采用免疫组织化学法评估CENPM蛋白表达。在ACC（H295R和SW-13）细胞和异种移植NPG小鼠中验证CENPM对转移行为的影响。进行数据独立分析（DIA）定量蛋白质组学分析、蛋白质免疫印迹法、免疫荧光法和免疫共沉淀试验，以鉴定CENPM的下游靶点。 结果：在分析的12035个基因中，363个基因与ACC转移相关，CENPM被鉴定为核心基因。CENPM在ACC样本中上调，与转移和不良预后相关。敲低CENPM可抑制ACC细胞的增殖、侵袭和迁移，并抑制异种移植NPG小鼠的肝转移。敲低CENPM时，含胶原蛋白的细胞外基质信号主要下调。FGL1是细胞外基质信号的重要组成部分和LAG3的免疫检查点配体，在CENPM沉默后下调，在人类晚期ACC样本中过表达，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敲低的ACC细胞的迁移和侵袭。 结论：CENPM是驱动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。 要点：CENPM是驱动ACC转移的关键基因，是ACC预后的可靠生物标志物。通过与免疫检查点配体FGL1的物理相互作用，沉默CENPM可在体外和体内阻碍ACC转移。FGL1在ACC中过表达并促进ACC转移。
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