NTN4 As a Prognostic Marker and a Hallmark for Immune Infiltration in Breast Cancer

Overview

Journal Sci Rep

Specialty Science

Date 2022 Jun 22

PMID 35732855

Authors

Lili Yi

Yongqiang Lei

Fengjiao Yuan

Conghui Tian

Jian Chai

Mingliang Gu

Affiliations

Soon will be listed here.

Abstract

Netrin-4 (NTN4), a member of neurite guidance factor family, can promote neurite growth and elongation. This study aims to investigate if NTN4 correlates with prognosis and immune infiltration in breast cancer. The prognostic landscape of NTN4 and its relationship with immune infiltration in breast cancer were deciphered with public databases and immunohistochemistry (IHC) in tissue samples. The expression profiling and prognostic value of NTN4 were explored using UALCAN, TIMER, Kaplan-Meier Plotter and Prognoscan databases. Based on TIMER, relationships of NTN4 expression with tumor immune invasion and immune cell surface markers were evaluated. Transcription and survival analyses of NTN4 in breast cancer were investigated with cBioPortal database. The STRING database was explored to identify molecular functions and signaling pathways downstream of NTN4. NTN4 expression was significantly lower in invasive breast carcinoma compared with adjacent non-malignant tissues. Promoter methylation of NTN4 exhibited different patterns in breast cancer. Low expression of NTN4 was associated with poorer survival. NTN4 was significantly positively related to infiltration of CD8 T cells, macrophages and neutrophils, whereas significantly negatively related to B cells and tumor purity. Association patterns varied with different subtypes. Various associations between NTN4 levels and immune cell surface markers were revealed. Different subtypes of breast cancer carried different genetic alterations. Mechanistically, NTN4 was involved in mediating multiple biological processes including morphogenesis and migration.

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References

Fumet J, Truntzer C, Yarchoan M, Ghiringhelli F . Tumour mutational burden as a biomarker for immunotherapy: Current data and emerging concepts. Eur J Cancer. 2020; 131:40-50. PMC: 9473693. DOI: 10.1016/j.ejca.2020.02.038. View

Li T, Fan J, Wang B, Traugh N, Chen Q, Liu J . TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 2017; 77(21):e108-e110. PMC: 6042652. DOI: 10.1158/0008-5472.CAN-17-0307. View

Hebrok M, Reichardt L . Brain meets pancreas: netrin, an axon guidance molecule, controls epithelial cell migration. Trends Cell Biol. 2004; 14(4):153-5. PMC: 2744962. DOI: 10.1016/j.tcb.2004.02.005. View

Koch M, Murrell J, Hunter D, OLSON P, Jin W, Keene D . A novel member of the netrin family, beta-netrin, shares homology with the beta chain of laminin: identification, expression, and functional characterization. J Cell Biol. 2000; 151(2):221-34. PMC: 2192657. DOI: 10.1083/jcb.151.2.221. View

Chen B, Wei W, Huang X, Xie X, Kong Y, Dai D . circEPSTI1 as a Prognostic Marker and Mediator of Triple-Negative Breast Cancer Progression. Theranostics. 2018; 8(14):4003-4015. PMC: 6071524. DOI: 10.7150/thno.24106. View

Shimizu A, Nakayama H, Wang P, Konig C, Akino T, Sandlund J . Netrin-1 promotes glioblastoma cell invasiveness and angiogenesis by multiple pathways including activation of RhoA, cathepsin B, and cAMP-response element-binding protein. J Biol Chem. 2012; 288(4):2210-22. PMC: 3554894. DOI: 10.1074/jbc.M112.397398. View

Konig I, Fuchs O, Hansen G, von Mutius E, Kopp M . What is precision medicine?. Eur Respir J. 2017; 50(4). DOI: 10.1183/13993003.00391-2017. View

Esseghir S, Kennedy A, Seedhar P, Nerurkar A, Poulsom R, Reis-Filho J . Identification of NTN4, TRA1, and STC2 as prognostic markers in breast cancer in a screen for signal sequence encoding proteins. Clin Cancer Res. 2007; 13(11):3164-73. DOI: 10.1158/1078-0432.CCR-07-0224. View

Yang Y, Szabat M, Bragagnini C, Kott K, Helgason C, Hoffman B . Paracrine signalling loops in adult human and mouse pancreatic islets: netrins modulate beta cell apoptosis signalling via dependence receptors. Diabetologia. 2011; 54(4):828-42. DOI: 10.1007/s00125-010-2012-5. View

10.

Larrieu-Lahargue F, Welm A, Thomas K, Li D . Netrin-4 induces lymphangiogenesis in vivo. Blood. 2010; 115(26):5418-26. PMC: 2902137. DOI: 10.1182/blood-2009-11-252338. View

11.

Lejmi E, Leconte L, Pedron-Mazoyer S, Ropert S, Raoul W, Lavalette S . Netrin-4 inhibits angiogenesis via binding to neogenin and recruitment of Unc5B. Proc Natl Acad Sci U S A. 2008; 105(34):12491-6. PMC: 2518829. DOI: 10.1073/pnas.0804008105. View

12.

Tang H, Huang X, Wang J, Yang L, Kong Y, Gao G . circKIF4A acts as a prognostic factor and mediator to regulate the progression of triple-negative breast cancer. Mol Cancer. 2019; 18(1):23. PMC: 6369546. DOI: 10.1186/s12943-019-0946-x. View

13.

Liu Y, Stein E, Oliver T, Li Y, Brunken W, Koch M . Novel role for Netrins in regulating epithelial behavior during lung branching morphogenesis. Curr Biol. 2004; 14(10):897-905. PMC: 2925841. DOI: 10.1016/j.cub.2004.05.020. View

14.

Yebra M, Diaferia G, Montgomery A, Kaido T, Brunken W, Koch M . Endothelium-derived Netrin-4 supports pancreatic epithelial cell adhesion and differentiation through integrins α2β1 and α3β1. PLoS One. 2011; 6(7):e22750. PMC: 3146510. DOI: 10.1371/journal.pone.0022750. View

15.

Paradisi A, Maisse C, Coissieux M, Gadot N, Lepinasse F, Delloye-Bourgeois C . Netrin-1 up-regulation in inflammatory bowel diseases is required for colorectal cancer progression. Proc Natl Acad Sci U S A. 2009; 106(40):17146-51. PMC: 2761333. DOI: 10.1073/pnas.0901767106. View

16.

Mizuno H, Kitada K, Nakai K, Sarai A . PrognoScan: a new database for meta-analysis of the prognostic value of genes. BMC Med Genomics. 2009; 2:18. PMC: 2689870. DOI: 10.1186/1755-8794-2-18. View

17.

J van t Veer L, Dai H, van de Vijver M, He Y, Hart A, Mao M . Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002; 415(6871):530-6. DOI: 10.1038/415530a. View

18.

Chandrashekar D, Bashel B, Balasubramanya S, Creighton C, Ponce-Rodriguez I, Chakravarthi B . UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses. Neoplasia. 2017; 19(8):649-658. PMC: 5516091. DOI: 10.1016/j.neo.2017.05.002. View

19.

Gyorffy B, Lanczky A, Eklund A, Denkert C, Budczies J, Li Q . An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2009; 123(3):725-31. DOI: 10.1007/s10549-009-0674-9. View

20.

Chen B, Tang H, Chen X, Zhang G, Wang Y, Xie X . Transcriptomic analyses identify key differentially expressed genes and clinical outcomes between triple-negative and non-triple-negative breast cancer. Cancer Manag Res. 2019; 11:179-190. PMC: 6306052. DOI: 10.2147/CMAR.S187151. View