Identification of CENPM As a Key Gene Driving Adrenocortical Carcinoma Metastasis Via Physical Interaction with Immune Checkpoint Ligand FGL1

Overview

Journal Clin Transl Med

Publisher Wiley

Date 2025 Jan 8

PMID 39778025

Authors

Cunru Zou

Yu Zhang

Chengyue Liu

Yaxin Li

Congjie Lin

Hao Chen

Jiangping Hou

Guojun Gao

Zheng Liu

Qiupeng Yan

Wenxia Su

Affiliations

Soon will be listed here.

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.

Citing Articles

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

Zou C, Zhang Y, Liu C, Li Y, Lin C, Chen H Clin Transl Med. 2025; 15(1):e70182.

PMID: 39778025 PMC: 11707433. DOI: 10.1002/ctm2.70182.

References

Zheng S, Cherniack A, Dewal N, Moffitt R, Danilova L, Murray B . Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma. Cancer Cell. 2016; 29(5):723-736. PMC: 4864952. DOI: 10.1016/j.ccell.2016.04.002. View

Libe R . Clinical and molecular prognostic factors in adrenocortical carcinoma. Minerva Endocrinol. 2018; 44(1):58-69. DOI: 10.23736/S0391-1977.18.02900-0. View

Ghosh C, Hu J, Kebebew E . Advances in translational research of the rare cancer type adrenocortical carcinoma. Nat Rev Cancer. 2023; 23(12):805-824. DOI: 10.1038/s41568-023-00623-0. View

Li J, Wang J, Tian T, Liu J, Zheng Y, Mo H . The liver microenvironment orchestrates FGL1-mediated immune escape and progression of metastatic colorectal cancer. Nat Commun. 2023; 14(1):6690. PMC: 10593839. DOI: 10.1038/s41467-023-42332-0. View

Tucker J, Carlsen C, Scribano C, Pattaswamy S, Burkard M, Weaver B . CENP-E Inhibition Induces Chromosomal Instability and Synergizes with Diverse Microtubule-Targeting Agents in Breast Cancer. Cancer Res. 2024; 84(16):2674-2689. PMC: 11326998. DOI: 10.1158/0008-5472.CAN-23-3332. View

Gaujoux S, Grabar S, Fassnacht M, Ragazzon B, Launay P, Libe R . β-catenin activation is associated with specific clinical and pathologic characteristics and a poor outcome in adrenocortical carcinoma. Clin Cancer Res. 2010; 17(2):328-36. DOI: 10.1158/1078-0432.CCR-10-2006. View

Xi F, Sun H, Peng H, Lian Z, Wei H, Tian Z . Hepatocyte-derived FGL1 accelerates liver metastasis and tumor growth by inhibiting CD8+ T and NK cells. JCI Insight. 2024; 9(13). PMC: 11383586. DOI: 10.1172/jci.insight.173215. View

Wang Q, Xu J, Xiong Z, Xu T, Liu J, Liu Y . CENPA promotes clear cell renal cell carcinoma progression and metastasis via Wnt/β-catenin signaling pathway. J Transl Med. 2021; 19(1):417. PMC: 8502268. DOI: 10.1186/s12967-021-03087-8. View

Singh P, Pesenti M, Maffini S, Carmignani S, Hedtfeld M, Petrovic A . BUB1 and CENP-U, Primed by CDK1, Are the Main PLK1 Kinetochore Receptors in Mitosis. Mol Cell. 2020; 81(1):67-87.e9. PMC: 7837267. DOI: 10.1016/j.molcel.2020.10.040. View

10.

Berthon A, Sahut-Barnola I, Lambert-Langlais S, De Joussineau C, Damon-Soubeyrand C, Louiset E . Constitutive beta-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development. Hum Mol Genet. 2010; 19(8):1561-76. DOI: 10.1093/hmg/ddq029. View

11.

Zheng C, Zhang T, Li D, Huang C, Tang H, Ni X . Upregulation of CENPM facilitates tumor metastasis via the mTOR/p70S6K signaling pathway in pancreatic cancer. Oncol Rep. 2020; 44(3):1003-1012. PMC: 7388243. DOI: 10.3892/or.2020.7673. View

12.

Erickson L, Rivera M, Zhang J . Adrenocortical carcinoma: review and update. Adv Anat Pathol. 2014; 21(3):151-9. DOI: 10.1097/PAP.0000000000000019. View

13.

Xiao Y, Najeeb R, Ma D, Yang K, Zhong Q, Liu Q . Upregulation of CENPM promotes hepatocarcinogenesis through mutiple mechanisms. J Exp Clin Cancer Res. 2019; 38(1):458. PMC: 6839178. DOI: 10.1186/s13046-019-1444-0. View

14.

Kai F, Drain A, Weaver V . The Extracellular Matrix Modulates the Metastatic Journey. Dev Cell. 2019; 49(3):332-346. PMC: 6527347. DOI: 10.1016/j.devcel.2019.03.026. View

15.

Assie G, Letouze E, Fassnacht M, Jouinot A, Luscap W, Barreau O . Integrated genomic characterization of adrenocortical carcinoma. Nat Genet. 2014; 46(6):607-12. DOI: 10.1038/ng.2953. View

16.

Ayala-Ramirez M, Jasim S, Feng L, Ejaz S, Deniz F, Busaidy N . Adrenocortical carcinoma: clinical outcomes and prognosis of 330 patients at a tertiary care center. Eur J Endocrinol. 2013; 169(6):891-899. PMC: 4441210. DOI: 10.1530/EJE-13-0519. View

17.

Rygiel T, Stolte E, de Ruiter T, van de Weijer M, Meyaard L . Tumor-expressed collagens can modulate immune cell function through the inhibitory collagen receptor LAIR-1. Mol Immunol. 2011; 49(1-2):402-6. DOI: 10.1016/j.molimm.2011.09.006. View

18.

Borges K, Pignatti E, Leng S, Kariyawasam D, Ruiz-Babot G, Ramalho F . Wnt/β-catenin activation cooperates with loss of p53 to cause adrenocortical carcinoma in mice. Oncogene. 2020; 39(30):5282-5291. PMC: 7378041. DOI: 10.1038/s41388-020-1358-5. View

19.

Andrews L, Marciscano A, Drake C, Vignali D . LAG3 (CD223) as a cancer immunotherapy target. Immunol Rev. 2017; 276(1):80-96. PMC: 5338468. DOI: 10.1111/imr.12519. View

20.

Chen T, Ma J, Liu Y, Chen Z, Xiao N, Lu Y . iProX in 2021: connecting proteomics data sharing with big data. Nucleic Acids Res. 2021; 50(D1):D1522-D1527. PMC: 8728291. DOI: 10.1093/nar/gkab1081. View